Clinical Review & Education

JAMA | Review

Diagnosis and Treatment of Pulmonary Arterial Hypertension

A Review
Nicole F. Ruopp, MD; Barbara A. Cockrill, MD

Multimedia
IMPORTANCE Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH),
characterized by pulmonary arterial remodeling. The prevalence of PAH is approximately 10.6 cases
per 1 million adults in the US. Untreated, PAH progresses to right heart failure and death.

OBSERVATIONS Pulmonary hypertension is defined by a mean pulmonary artery pressure

greater than 20 mm Hg and is classified into 5 clinical groups based on etiology, pathophysiology,
and treatment. Pulmonary arterial hypertension is 1 of the 5 groups of PH and is
hemodynamically defined by right heart catheterization demonstrating a mean pulmonary
artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg
or lower, and a pulmonary vascular resistance of 3 Wood units or greater. Pulmonary arterial
hypertension is further divided into subgroups based on underlying etiology, consisting of
idiopathic PAH, heritable PAH, drug- and toxin-associated PAH, pulmonary veno-occlusive
disease, PAH in long-term responders to calcium channel blockers, and persistent PH of the
newborn, as well as PAH associated with other medical conditions including connective tissue
disease, HIV, and congenital heart disease. Early presenting symptoms are nonspecific and
typically consist of dyspnea on exertion and fatigue. Currently approved therapy for PAH consists
of drugs that enhance the nitric oxide–cyclic guanosine monophosphate biological pathway
(sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (epoprostenol or treprostinil),
and endothelin pathway antagonists (bosentan and ambrisentan). With these PAH-specific Author Affiliations: Pulmonary,
therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. Current Critical Care, and Sleep Medicine,
treatment consists of combination drug therapy that targets more than 1 biological pathway, Tufts Medical Center, Boston,
Massachusetts (Ruopp); Pulmonary
such as the nitric oxide–cyclic guanosine monophosphate and endothelin pathways and Critical Care Medicine, Brigham
(eg, ambrisentan and tadalafil), and has shown demonstrable improvement in morbidity and and Women’s Hospital, Harvard
mortality compared with the previous conventional single-pathway targeted monotherapy. Medical School, Boston,
Massachusetts (Cockrill).
CONCLUSIONS AND RELEVANCE Pulmonary arterial hypertension affects an estimated 10.6 per Corresponding Author: Nicole F.
1 million adults in the US and, without treatment, typically progresses to right heart failure Ruopp, MD, Pulmonary, Critical Care,
and death. First-line therapy with drug combinations that target multiple biological pathways and Sleep Medicine, Tufts Medical
Center, 800 Washington St,
are associated with improved survival.
No. 257, Boston, MA 02111
(nruopp@tuftsmedicalcenter.org).
JAMA. 2022;327(14):1379-1391. doi:10.1001/jama.2022.4402 Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.

P
ulmonary arterial hypertension (PAH) is a life-threatening arterial hypertension. Articles were selected for inclusion based on
disorder characterized by elevated pressure in the pulmo- relevance to current clinical practice. Randomized clinical trials, large
nary arteries due to increased pulmonary vascular longitudinal observational studies, and more recent articles were pri-
resistance.1 Symptoms of PAH are nonspecific but commonly in- oritized. Bibliographies of retrieved articles were searched for other
clude dyspnea on exertion and fatigue.2 The estimated prevalence relevant articles. Of the articles identified, 99 were included, con-
of PAH is 10.6 per 1 million adults in the US. Untreated, PAH typi- sisting of 23 randomized clinical trials, 3 meta-analyses and system-
cally progresses to right ventricular failure and death.3 Treatment atic reviews, 36 observational studies, 16 registry-based studies, and
has significantly improved outcomes in the last decade.4 The diag- 21 clinical practice guidelines or other reports.
nosis should be considered in any patient presenting with unex-
plained exertional dyspnea. This Review summarizes current evi-
dence regarding diagnosis and treatment of PAH.
Definition and Classification
of Pulmonary Hypertension
The clinical classification of pulmonary hypertension (PH), of which
Methods
PAH is a subtype, is important for understanding the approach to
PubMed was searched for English-language articles from 1985 both diagnosis and treatment of PAH. Pulmonary hypertension is
through December 30, 2021, using search terms for pulmonary currently defined by a mean pulmonary artery pressure greater than

jama.com (Reprinted) JAMA April 12, 2022 Volume 327, Number 14 1379

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Clinical Review & Education Review Diagnosis and Treatment of Pulmonary Arterial Hypertension

Figure 1. Classification of Pulmonary Hypertension and Pathophysiology of Pulmonary Arterial Hypertension

A Classification of pulmonary hypertension (PH)

1 - Pulmonary arterial hypertension (PAH) 2 - PH due to left heart disease 4 - PH due to pulmonary artery obstructions
1.1 Idiopathic 2.1 Heart failure with preserved LVEF 4.1 Chronic thromboembolic PH
1.2 Heritable 2.2 Heart failure with reduced LVEF 4.2 Other pulmonary artery obstructions
1.3 Drug- and toxin-induced 2.3 Valvular heart disease
Congenital or acquired cardiovascular conditions
5 - PH with unclear and/or
1.4 Associated with other conditions: 2.4
connective tissue disease, HIV infection, portal leading to postcapillary PH mutifactorial mechanisms
hypertension, congenital heart disease, schistosomiasis 3 - PH due to lung disease and/or hypoxia 5.1 Hematological disorders (eg, sickle cell disease)
1.5 Long-term responders to calcium channel blockers 5.2 Systemic disorders (eg, sarcoidosis) and
3.1 Obstructive lung disease metabolic disorders (eg, Gaucher disease)
1.6 With overt features of venous/capillary involvement
(eg, pulmonary veno-occlusive disease) 3.2 Restrictive lung disease 5.3 Others (eg, fibrosing mediastinitis)
1.7 Persistent PH of the newborn 3.3 Other lung disease with restrictive/obstructive pattern 5.4 Complex congenital heart disease
(eg, combined pulmonary fibrosis and emphysema)
3.4 Hypoxia without lung disease (eg, obesity-hypoventilation)
B Precapillary and postcapillary PH 3.5 Developmental lung disease

P U L M O N A RY C I R C U L AT I O N Pulmonary arteries and arterioles Capillaries Pulmonary venules and veins

Precapillary PH due to increased resistance Postcapillary PH due to increased pressure

to pulmonary arterial blood flow proximal or resistance to blood flow distal to pulmonary
to pulmonary capillaries capillaries (commonly due to left heart disease)
PAP >20 mm Hg PAWP ≤ 15 mm Hg PVR ≥3 WU PAP >20 mm Hg PAWP >15 mm Hg PVR ≥3 WU
Always present in PAH, may be present in other groups Always present in PH group 2

C Pathophysiology of PAH Small pulmonary arteries and arterioles in PAH

Healthy small pulmonary arteries and arterioles Remodeling and thickening of arterial walls along with vasoconstriction cause
vessel lumen narrowing, increased resistance to blood flow, and decreased vessel
compliance leading to increased pulmonary arterial pressure.

Adventitia
Increased resistance
Media to blood flow

Intima
Elastic lamina
Endothelium deterioration
Internal elastic lamina
Endothelial
Smooth muscle Blood flow hyperplasia
under normal Plexiform lesion
External elastic lamina vascular resistance Smooth muscle
hypertrophy Plexiform lesions are webs of small, irregular vascular channels
separated by fibrous tissue and are characteristic of severe PAH.

LVEF indicates left ventricular ejection fraction; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; WU, Wood units.

20 mm Hg on supine right heart catheterization at rest.5 This defi-

nition differs from the previous threshold of 25 mm Hg or greater Pathophysiology of PAH
in recognition that patients with a mean pulmonary artery pres-
sure of 21 mm Hg to 24 mm Hg are at increased risk of mortality and Distinguishing between PH due to prepulmonary vs postpulmo-
hospitalization compared with those with a mean pulmonary ar- nary capillary vascular abnormalities is essential to understanding
tery pressure of 20 mm Hg or lower.6 the pathophysiology of PAH (Figure 1B). Pulmonary hypertension
Pulmonary hypertension is classified into 5 groups (Figure 1A). is defined by elevation of the pressure within the pulmonary arter-
Group 1 PH (PAH) is defined as a mean pulmonary artery pressure ies. Normally, cardiac output from the right ventricle flows through
greater than 20 mm Hg, pulmonary artery wedge pressure of the pulmonary arteries and arterioles, pulmonary capillaries, pul-
15 mm Hg or lower, and pulmonary vascular resistance of 3 Wood monary venules, and veins, eventually reaching the left atrium. Pre-
units or greater.5 Group 2 is PH associated with left heart disease. capillary PH exists when the elevation in pulmonary artery pres-
Group 3 is PH associated with lung disease such as chronic obstruc- sure is due to increased resistance in the pulmonary arteries proximal
tive pulmonary disease or idiopathic pulmonary fibrosis and/or hy- to the pulmonary capillaries, and is always present in PAH.
poxemia. Group 4 disease is PH due to pulmonary artery obstruc- The pathophysiologic mechanisms of PAH remain unclear.5,8,9
tion, typically chronic thromboembolic disease. Group 5 is PH Vascular pathology consists of arterial medial and intimal remodel-
associated with an unclear cause or multifactorial causes. Thus, all ing, plexiform lesions, and fragmentation of the elastic lamina
PAH, the subject of this Review, is also classified as PH, whereas only (Figure 1C).8,9 Vascular remodeling, defined as thickening of the vas-
Group 1 PH is considered PAH.5,7 cular wall via hypertrophy or hyperplasia, primarily contributes to

1380 JAMA April 12, 2022 Volume 327, Number 14 (Reprinted) jama.com

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Diagnosis and Treatment of Pulmonary Arterial Hypertension Review Clinical Review & Education

increased pulmonary vascular resistance and, subsequently, an in- tially diagnosed with idiopathic PAH, underscoring the need for
crease in mean pulmonary artery pressure. Vasoconstriction is an genetic counseling for patients who have either heritable or idio-
important component of PAH; however, whether it is an inciting pathic PAH.18 Currently, approximately 15 additional variants have
event or a complication of pulmonary vascular remodeling is been identified in people with heritable PAH,19 including variants
uncertain.8 Eventually, the small precapillary arteries and arteri- present in hereditary hemorrhagic telangiectasia.20 Compared with
oles are obliterated, leading to an isolated reduction in diffusing ca- nonheritable idiopathic PAH, heritable PAH due to BMPR2 variants
pacity for carbon monoxide (DLCO) in patients with PAH.10 Effec- typically presents earlier (age 37 years vs age 46 years), has more
tive treatments ideally target remodeling of pulmonary arteries as severe hemodynamic characteristics at diagnosis, and has a poorer
well as vasoconstriction. Initially, the right ventricle compensates for response rate to therapy.21,22
increased afterload by increasing contractility and wall thickness.
Eventually, the right ventricle dilates and fails, resulting in death due Drug- and Toxin-Induced PAH (Group 1.3)
to right heart failure if left untreated.11 Pulmonary arterial hypertension is associated with specific drug
and toxin exposures, such as methamphetamine, dasatinib, or
fenfluramine.5 A study of patients hospitalized from 2003 to
2015 reported that the incidence of likely PAH-related hospitaliza-
Prevalence of PAH and Patient Characteristics
tion per International Classification of Diseases coding was more
Pulmonary arterial hypertension is uncommon. A French registry than twice as high in users vs nonusers of methamphetamine
(n = 674; 2002-2003) reported an incidence of about 2.4 cases per (984.6 cases per 1 million [meth]amphetamine users compared
1 million per year and a prevalence of 15 cases per 1 million adults.12 with 373.2 cases per 1 million in non-[meth]amphetamine users;
The US-based REVEAL registry (n = 2525; 2006-2007), a multi- relative risk [RR], 2.64; 95% CI, 2.18-3.2; P < .001). 23 In 90
center prospective cohort study involving 54 centers, reported an patients with methamphetamine-associated PAH and 97 patients
incidence of 2.0 cases per 1 million per year and a prevalence with idiopathic PAH, those with methamphetamine-associated
of 10.6 cases per 1 million adults.1 PAH had more severe clinical disease and rapid progression of
Patient characteristics vary by registry. In contrast to findings PAH compared with those with idiopathic PAH (5-year and
from a National Institutes of Health registry initiated in 1981 10-year event-free survival rates of 47.2% and 25% vs 64.5% and
(n = 187),13 the REVEAL registry (n = 2525; 2006-2007) reported 45.7%, respectively).23
that patients with PAH were older (aged 50.1 [SD, 14.4] years vs 35 Dasatinib, a targeted cancer therapy tyrosine kinase inhibitor,
[SD, 15] years at diagnosis) and had a greater predominance among is associated with development of PAH. In a French registry of 2900
women (ratio of female to male patients, 4.07:1 vs 1.7:1).1,14 It is un- patients receiving dasatinib, 9 patients developed PH (mean length
certain whether these differences represent temporal changes in of treatment prior to diagnosis, 31 months; range, 8-48 months), and
characteristics of people with PAH or are related to increased 4 additional cases of dasatinib-associated PH were reported to
awareness.14 Prior to the development of PAH-specific therapy, French regulatory agencies; therefore, the lowest estimate of PH in
5-year survival after diagnosis was 34% (n = 187).3 More recent data patients with a history of dasatinib use was 0.45%, compared with
reported 1-year survival rates of approximately 61% (REVEAL reg- 10 to 15 cases per 1 million in a population that was not associated
istry; n = 2749; 2006-2009) and 64% (French registry; n = 1611; with use of dasatinib.24 Dasatinib-associated PAH typically re-
2006-2018).15,16 solves with discontinuation of the drug.25,26 In a pharmaceutical vigi-
lance database, 34 of 36 patients with dasatinib-associated PAH had
improvement or resolution of their symptoms with discontinua-
tion of the drug.27
Subgroups of PAH
Pulmonary arterial hypertension is further categorized into subgroups Associated PAH (Group 1.4)
based on pathophysiology, etiology, and response to treatment. Connective Tissue Disease–Associated PAH (Group 1.4.1)
Connective tissue disease–associated PAH affects 15% to 25% of
Idiopathic PAH (Group 1.1) people with PAH, most commonly patients with scleroderma,
Previously referred to as primary PH, idiopathic PAH meets the he- although it also occurs with systemic lupus erythematosus,
modynamic criteria for PAH but is not associated with another dis- mixed connective tissue disease, rheumatoid arthritis, and Sjögren
ease process, such as collagen vascular disease or liver disease. The syndrome.1,12,14 The prevalence of PAH in patients with sclero-
REVEAL registry and French registry reported that 46% of 2525 pa- derma is 8% to 14%.24,28 Patients with scleroderma-associated
tients with PAH and 39% of 674 patients with PAH had idiopathic PAH have a worse prognosis compared with other forms of con-
PAH, respectively.1,12 nective tissue disease–associated PAH and have a higher preva-
lence of pericardial effusions, shorter 6-minute walk distance, and
Heritable PAH (Group 1.2) worse DLCO compared with people with idiopathic PAH.29 Patients
Heritable PAH (or familial PAH) affects approximately 6% to 10% of with scleroderma who have PAH have a higher rate of mortality
people with PAH.17 Variants in the bone morphogenetic protein than those without PAH (3-year survival, 94% vs 56%; n = 546).30
receptor 2 gene (BMPR2) account for nearly 75% of heritable PAH Annual echocardiogram screening is recommended by the
and are associated with an autosomal dominant/incomplete pen- World Symposium on Pulmonary Hypertension for patients
etrance pattern of inheritance.18 When genotyping is performed, with scleroderma to facilitate early diagnosis and treatment
BMPR2 variants are present in approximately 25% of patients ini- of PAH.2,30,31 However, no clinical trials have shown that annual

jama.com (Reprinted) JAMA April 12, 2022 Volume 327, Number 14 1381

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Clinical Review & Education Review Diagnosis and Treatment of Pulmonary Arterial Hypertension

echocardiogram screening improves outcomes. A cross-sectional Schistosomiasis-Associated PAH (Group 1.4.5)

international study of 466 patients with scleroderma at high risk of Schistosomiasis-associated PAH represents the leading cause of PAH
PAH found that 87 of 466 patients (19%) had PAH confirmed by in countries where schistosomiasis is endemic, thus possibly repre-
right heart catheterization.32 senting the largest burden of PAH worldwide.43,44 Among patients
with severe schistosomal liver disease, approximately 5% to 8% de-
HIV-Associated PAH (Group 1.4.2) velop schistosomiasis-associated PAH. 45 Schistosomiasis-
Pulmonary arterial hypertension is a potential complication of HIV associated PAH should be considered or suspected in patients with
infection. In 7658 patients with HIV infection, the prevalence of PAH who are from an endemic area and who have Schistosoma para-
PAH was 0.46% (95% CI, 0.32%-0.64%), compared with 10 to 15 site eggs in stool, a history of treatment for schistosomiasis, or ultra-
cases per 1 million in a population that was not HIV positive.33 sound evidence of hepatosplenic schistosomiasis, such as portal hy-
Echocardiographic assessment is recommended by the World Sym- pertension with portal fibrosis with or without splenomegaly.44,46
posium on Pulmonary Hypertension in all patients with HIV infec-
tion with unexplained dyspnea or in patients with asymptomatic PAH in Long-term Responders to Calcium Channel Blockers
HIV infection who have additional risk factors such as female sex, (Group 1.5)
intravenous drug or cocaine use, or hepatitis C infection.2 However, First recognized in 2018, long-term responders to calcium channel
this approach has not been shown to improve outcomes in patients blockers are defined as patients with PAH who demonstrate acute
with HIV. vasodilation of the pulmonary vasculature in response to inhaled ni-
tric oxide challenge and improvement in New York Heart Associa-
Portal Hypertension–Associated PAH (Group 1.4.3) tion function class (to class I or II) and unchanged or improved hemo-
Portopulmonary hypertension, defined as PAH in association with dynamics at 1 year when treated with calcium channel blockers alone.5
portal hypertension, can develop in patients with portal hyper- Acute vasodilator testing is performed during right heart catheter-
tension due to cirrhosis, periportal fibrosis without cirrhosis, por- ization, with measurement of hemodynamics typically before and af-
tal vein thrombosis, hepatic vein sclerosis, and congenital portal ter inhaled nitric oxide. Testing may alternatively be performed with
circulation abnormalities. Survival is worse with portopulmonary inhaled or intravenous epoprostenol, adenosine, or inhaled iloprost.
hypertension when cirrhosis is present.34 In a prospective study A positive test result is defined as a decrease in mean pulmonary ar-
of 1235 patients evaluated for liver transplant, PAH was diag- tery pressure by 10 mm Hg or greater to less than 40 mm Hg without
nosed in 5%.35 The pathophysiologic connection between portal a decrease in cardiac output.5 In a study of 557 patients with PAH,
hypertension and PAH is unclear. It is hypothesized that the dys- 12.5% had an acute vasodilator response and 6.8% had a sustained
functional liver and portosystemic shunts expose the pulmonary response with long-term improvement while taking calcium channel
vascular bed to factors that may adversely affect it via abnormal blockers.47 Patients with long-term calcium channel blocker respon-
estrogen signaling in genetically susceptible individuals.36,37 Prac- siveness possess unique molecular signatures in human lung fibro-
tice guidelines recommend obtaining an echocardiogram in all blasts enriched for vascular smooth muscle–related genes that dif-
patients with portal hypertension to assess for PH, although this ferentiate them from non–calcium channel blocker–responsive
approach has not been shown to improve clinical outcomes.2 The idiopathic PAH.48 Survival is better for patients with PAH who are long-
American Society of Transplantation recommends screening for term responders to calcium channel blockers.47,49
portopulmonary hypertension with echocardiogram as part of a
comprehensive evaluation prior to liver transplant.35,38 Portopul- PAH With Overt Features of Venous/Capillary Involvement
monary hypertension may improve or resolve following liver (Group 1.6)
transplant. In a 10-year follow-up study of patients with portopul- Pulmonary veno-occlusive disease and pulmonary capillary he-
monary hypertension who underwent liver transplant (n = 27), mangiomatosis account for 5% to 10% of patients initially diag-
45% had resolution of PH while 55% required ongoing pulmonary nosed as having idiopathic PAH (estimated incidence of 0.1 to 0.2
vasodilator therapy.39 cases per 1 million; prevalence of 1 case per 1 million).40,50 Patients
with pulmonary veno-occlusive disease or pulmonary capillary
Congenital Heart Disease–Associated PAH (Group 1.4.4) hemangiomatosis present with severe reductions in DLCO, severe
Congenital heart disease–associated PAH consists of a diverse hypoxemia, and typical imaging findings including diffuse septal
spectrum of pathophysiology and includes 4 subgroups: thickening, centrilobular ground-glass opacities, and mediastinal
Eisenmenger syndrome, PAH associated with systemic-to- lymphadenopathy.51 The distinction between pulmonary veno-
pulmonary shunts, PAH with small/coincidental cardiac defects occlusive disease and pulmonary capillary hemangiomatosis has
(such as small atrial septal defects or ventricular septal defects), been questioned since both have features of a pan-pulmonary
and PAH after cardiac defect closure.40 In 192 patients with con- vasculopathy with prominent septal vein/venule involvement and
genital heart disease–associated PAH, 20-year survival rates were capillary congestion/proliferation with varying degrees of small
87% for those with Eisenmenger syndrome, 86% for those with arteriolar involvement.50 Unlike idiopathic PAH, both entities have
systemic-to-pulmonary shunts, and 36% for those with corrected significant involvement of small vessels distal to the pulmonary
abnormalities such as atrial and ventricular septal defects.41 Sur- arterioles, which makes treatment with pulmonary vasodilators
vival in patients with Eisenmenger syndrome is better than that of dangerous due to the risk of precipitating pulmonary edema.52
patients with idiopathic PAH (89% vs 46%) at 10 years, possibly Heritable forms of pulmonary veno-occlusive disease and pulmo-
because of better right ventricular function in patients with nary capillary hemangiomatosis have been reported in association
Eisenmenger syndrome.41,42 with EIF2AK4 and BMPR2 variants.51,53

1382 JAMA April 12, 2022 Volume 327, Number 14 (Reprinted) jama.com

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Diagnosis and Treatment of Pulmonary Arterial Hypertension Review Clinical Review & Education

Figure 2. Diagnosis and Medical Management of Pulmonary Arterial Hypertension

Patient presents with unexplained exertional dyspnea

Initial testing to confirm diagnosis and classify the cause of pulmonary hypertension (PH)
• History and physical examination, complete blood count, chest x-ray, and electrocardiogram are performed to rule out other causes of dyspnea
• Additional testing may include pulmonary function testing, cardiac echocardiography, and assessment for myocardial ischemia
• Chronic thromboembolic pulmonary hypertension must be excluded before pulmonary arterial hypertension (PAH) diagnosis is definite

Confirmation of PAH diagnosis and assessment of disease severity with right heart catheterization

Patients with idiopathic, hereditary, or drug-induced PAH Patients with other subtypes of PAH
Perform acute vasoreactivity test to evaluate pulmonary artery
response to a pulmonary artery vasodilator (such as nitric oxide)
• Positive reactivity is defined as a decrease in mean pulmonary arterial
pressure by at least 10 mm Hg to below an absolute value of 40 mm Hg

POSITIVE NEGATIVE

Consider calcium Assess patient risk level for clinical worsening or death in order to guide initial therapy
channel blocker
therapy trial LOW RISKa INTERMEDIATE RISKa HIGH RISKa
• 1-year mortality <5% • 1-year mortality 5% -10% • 1-year mortality >10%
• No clinical signs of right • Clinical signs of moderately impaired • Clinical signs of severe RV dysfunction, or
ventricular (RV) dysfunction exercise capacity and RV dysfunction RV failure and secondary organ dysfunction

Begin initial oral combination therapyb Begin initial combination therapy that
or includes an intravenous prostacyclin
Consider monotherapyc with an endothelin receptor antagonist analogue (eg, treprostinil)
(eg, ambrisentan), phosphodiesterase 5 inhibitor (eg, tadalafil), guanylate
cyclase stimulator (riociguat), or oral prostacyclin analogue (selexipag)

Perform ongoing risk assessment with evaluation of symptoms and exercise capacity every 3-6 mo

LOW RISK INTERMEDIATE or HIGH RISK

Continue current therapy regimen Escalate to double or triple combination therapy

(addition of prostacyclin analogue recommended if not part of initial therapy)

Consider referral for lung transplant if there

is persistent right ventricular dysfunction

a
Risk assessment as defined in Galiè et al.40 antagonists have been found to be efficacious compared with placebo and/or
b
Oral combinations of ambrisentan and tadalafil; macitentan added monotherapy.
c
sequentially to sildenafil; selexipag added sequentially to phosphodiesterase 5 Monotherapy can be considered in very low-risk populations or in patients
inhibitors and/or endothelin receptor antagonists; or oral treprostinil added who have been stable with monotherapy for more than 1 to 2 years.
sequentially to phosphodiesterase 5 inhibitors and/or endothelin receptor

Persistent PH of the Newborn Syndrome (Group 1.7)

Persistent PH of the newborn syndrome occurs when fetal circula- Clinical Presentation
tion fails to transition from intrauterine circulation to extrauterine
circulation at birth, resulting in persistently elevated pulmonary vas- Symptoms of PAH may be nonspecific and have an insidious onset
cular resistance, low pulmonary blood flow, right-to-left shunting (Figure 2). In the National Institutes of Health registry of 187 people
across the patent ductus arteriosus and patent foramen ovale, and with PAH, dyspnea was the first symptom in 60%, although 98%
severe hypoxemia.54 The incidence of persistent PH of the new- reported dyspnea at the time of PAH diagnosis.13 Fatigue (19%), near
born syndrome is 0.18% (3277 cases per 1 781 156 live births), with syncope (5%), syncope (8%), and chest pain (7%) also occur
a mortality rate of 7.6% at 1-year follow-up for all newborns with per- (Box 1).13 With advanced disease, these symptoms may occur with
sistent PH of the newborn syndrome.55 minimal exertion or at rest.

jama.com (Reprinted) JAMA April 12, 2022 Volume 327, Number 14 1383

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Clinical Review & Education Review Diagnosis and Treatment of Pulmonary Arterial Hypertension

Box 1. Presenting Symptoms, Signs, and Echocardiogram Box 2. Commonly Asked Questions in Pulmonary Arterial
Findings in Pulmonary Arterial Hypertension Hypertension

Common Symptoms Can Pulmonary Arterial Hypertension Be Diagnosed With

Dyspnea on exertion an Echocardiogram?
Fatigue No. An echocardiogram is an excellent first test; however,
diagnosis of pulmonary arterial hypertension requires a right heart
Lower extremity edema
catheterization to accurately assess hemodynamic status and
Palpitations eliminate left heart disease as a contributor to elevated pulmonary
Lightheadedness artery pressure.
Syncope How Dangerous Is a Right Heart Catheterization?
When performed at a center with experience in the procedure,
Physical Signs
right heart catheterization is associated with a low risk of serious
Loud pulmonic component of second heart sound
complications (1.1%) or death (0.055%), even for patients with
Elevated jugular venous pressure significant right ventricular dysfunction.
Pulmonary artery tap
What Is the Initial Laboratory Evaluation of Pulmonary
Tricuspid regurgitation murmur Hypertension?
Lower extremity edema Initial tests should include complete blood count, basic metabolic
panel, thyrotropin, B-type natriuretic peptide or N-terminal
Ascites
pro–brain natriuretic peptide, antinuclear antibody, and liver
Echocardiogram Findings function tests. Additional autoimmune serologic testing, HIV
Elevated estimated right ventricular systolic pressure screening, and hepatitis panel screening can be obtained when
Right ventricular dilation PAH is diagnosed, if indicated.

Right ventricular dysfunction

Peak tricuspid regurgitant jet >2.8 m/s
Flattening of interventricular septum Electrocardiogram
Tricuspid annular plane systolic excursion <17 mm In 61 patients with PAH, 13% of electrocardiogram findings were
normal.58 Typical abnormalities include right axis deviation (79%),
right ventricular hypertrophy (87%), and right ventricular strain
Physical examination findings are subtle in early disease. Of 187 (74%).13 A prospectively validated diagnostic decision tree (n = 251)
patients, 93% had a loud second heart sound.13 Other distinctive find- found that electrocardiographic variables with the strongest diag-
ings (right-sided third heart sound, tricuspid regurgitation murmur, in- nostic accuracy for the presence of PAH on right heart catheteriza-
creased jugular venous distension, right ventricular heave) occur in tion were heart rate and right ventricular strain (sensitivity, 79%;
moreadvanceddisease.Asrightventriculardysfunctionworsens,lower specificity, 60%).59
extremity edema, abdominal distension, and ascites may develop.
Diagnosis is often delayed: 21.1% of patients in the REVEAL reg- Laboratory Testing
istry (n = 2967) had symptoms for more than 2 years before Plasma levels of N-terminal pro–brain natriuretic peptide (NT-proBNP)
diagnosis.56 Younger age (<36 years) and coexistence of common increase in patients with PAH and right ventricular dysfunction. El-
respiratory disorders such as asthma and obstructive sleep apnea evated NT-proBNP levels are associated with an increased risk of death
increase delayed diagnosis.56 Prognosis is associated with disease (n = 2017; hazard ratio, 1.84; 95% CI, 1.62-2.10; P < .001 [absolute rate
severity at presentation. Expert consensus recommends that early data were not included in the published article]).60 Laboratory test-
diagnosis and early initiation of therapy may improve survival.4,15 ing may help diagnose PAH associated with HIV/AIDS (HIV anti-
A high degree of clinical suspicion in a patient with unexplained ex- body), connective tissue disorder (positive antinuclear antibody >1:160
ertional dyspnea or fatigue is required. and other associated autoantibodies), or portopulmonary hyperten-
sion (liver function test abnormalities).2,40

Echocardiography
Assessment and Diagnosis
Two meta-analyses (n = 3947 and n = 4386) reported sensitivity and
Evaluation of patients with possible PH should focus on confirming specificity of echocardiographic assessment for presence of PH of
the diagnosis, classifying the cause of PH, and ascertaining severity approximately 85% and 70% to 74%, respectively.61,62 Echocardi-
(Box 2). If a thorough history, physical examination, complete blood ography-based estimates of pressure may be imprecise and may
count, chest x-ray, and electrocardiogram do not explain dyspnea, overestimate or underestimate true values.63,64 Right heart cath-
recommended testing may include pulmonary function tests, car- eterization should be considered for accurate measurement of pul-
diac echocardiography, and assessment for myocardial ischemia, de- monary artery pressure in the presence of other signs, including in-
pending on a patient’s history and risk factors.2,57 Chronic throm- creased tricuspid regurgitation velocity and/or signs of right
boembolic PH, defined by progressive pulmonary artery vascular ventricular pressure/volume overload such as right ventricular en-
remodeling leading to PH as a consequence of pulmonary embo- largement or dysfunction, flattening of the interventricular sep-
lism, must be excluded before PAH can be diagnosed.5,40 tum, or pulmonary artery enlargement.40 A retrospective study

1384 JAMA April 12, 2022 Volume 327, Number 14 (Reprinted) jama.com

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Diagnosis and Treatment of Pulmonary Arterial Hypertension Review Clinical Review & Education

(n = 1262) reported that the absence of significant tricuspid regur-

gitation on a transthoracic echocardiogram performed within 2 days Box 3. Right Heart Catheterization Diagnostic Testing
of a right heart catheterization had a negative predictive value for for Pulmonary Arterial Hypertension
excluding PH of 53%.65 This study was not limited to patients with • Verify mean pulmonary artery pressure >20 mm Hg.
suspected PAH, and the negative predictive value of a transtho- • Assess cardiac output and right ventricular function.
racic echocardiogram for PAH is not known. • Exclude postcapillary disease and confirm pulmonary artery
wedge pressure ⱕ15 mm Hg.
• Verify pulmonary vascular resistance >3 Wood units.
Pulmonary Function Testing
• Perform acute vasodilator testing if indicated (idiopathic,
Pulmonary vascular disease is characterized by normal spirometry
hereditary, and drug- and toxin-induced pulmonary arterial
findings, normal lung volumes, and a low DLCO due to destruction hypertension) to identify the subset of patients for whom
of the pulmonary vasculature.10 Of 79 consecutive patients with calcium channel blockers may be effective treatment.
documented PAH, 78% had a low DLCO.10 In a retrospective study
of 166 patients with PAH, DLCO values less than 45% were associ-
ated with 38% 5-year survival compared with 80% in those with Health Organization (WHO) functional class by at least 1 class in
a DLCO of 45% or greater.66 28% to 42% of patients, and mean pulmonary artery pressure by
2.1 mm Hg to 4.7 mm Hg.74 In a randomized clinical trial of 405
Specialty Center Evaluation patients, tadalafil improved 6-minute walk distance by 31 m com-
Care of patients with PAH is complex. Clinicians should consider re- pared with placebo.75
ferring patients with possible PH to a PH specialty center.2,67 In a ret-
rospective observational study of 580 patients within a 40- Soluble Guanylate Cyclase Stimulators
hospital system, after adjustment for age and comorbidities, care Soluble guanylate cyclase stimulators, such as oral riociguat, en-
at a specialty center is associated with decreased hospitalizations hance cyclic guanosine monophosphate production, causing vaso-
(hazard ratio, 0.68; P = .01 [absolute rate data were not included in dilation. In a randomized clinical trial of 444 patients, compared with
the published article]) and increased survival (incidence ratio, 0.54; placebo, riociguat improved WHO functional class (21% vs 14%;
P < .001).67 The retrospective design and lack of specific informa- P = .003), improved 6-minute walk distance by 30 m (P < .001), and
tion regarding possible referral bias are limitations of this study. reduced pulmonary vascular resistance by 223 dyne·s·cm −5
(P < .001).76 The combination of riociguat and phosphodiesterase
Right Heart Catheterization 5 inhibitors can cause severe hypotension and should be avoided.77
Right heart catheterization is required for definitive diagnosis of
PAH and to assess disease severity, which guides treatment Endothelin Receptor Antagonists
(Box 3).2,40 When performed at expert centers, the procedure has Endothelin 1, a potent endogenous vasoconstrictor, is overex-
a low morbidity (1.1%) and mortality (0.055%) (n = 7218).68 The pressed in the pulmonary vasculature of patients with PAH. Endo-
most common serious adverse effects from the procedure consist thelin receptor antagonists, such as bosentan and ambrisentan, block
of hematoma at puncture site (0.0014%), vagal reactions with bra- the activity of endothelin 1, resulting in vasodilation. In 2 random-
dycardia and hypotension (0.0015%), and supraventricular tachy- ized clinical trials of 32 and 213 participants, compared with pla-
cardia (0.001%).68 cebo, bosentan improved 6-minute walk distance by 44 m to 70 m
and WHO functional class in approximately 42% to 43% of
patients.78,79 Ambrisentan (n = 500) improved time to clinical wors-
ening and 6-minute walk distance while macitentan improved time
Medical Treatment for PAH to clinical worsening, defined as worsening of PAH, initiation of treat-
Current therapies for PAH pulmonary vasodilator treatment target ment with intravenous or subcutaneous prostanoids, lung trans-
3 pathways: stimulating the nitric oxide–cyclic guanosine mono- plant, or atrial septostomy.69,71
phosphate biological pathway, increasing prostacyclin effects on re-
ceptors, and antagonizing the endothelin pathway (Table 1). Medi- Prostacyclins and Prostacyclin Agonists
cal therapy with combinations of pulmonary vasodilators that target Prostacyclin, a potent pulmonary artery vasodilator, is endog-
multiple therapeutic pathways were superior to monotherapy- enously produced by endothelial cells. Synthetic prostacyclins
based regimens for outcomes of survival and time to clinical (epoprostenol, treprostinil, and iloprost) also cause vasodilation.
worsening.4,69-73 Treatment of PAH discussed herein does not ap- Epoprostenol remains the only pulmonary vasodilator to demon-
ply to patients with non–Group 1 PH, particularly Group 2 and Group strate a mortality benefit in a clinical trial of 82 people randomized
3 disease, for which treatment with pulmonary vasodilators re- to receive epoprostenol or placebo (mortality rate, 0% vs 5%;
mains controversial. P = .003).80 Treprostinil increases time to clinical worsening and im-
proves symptoms and 6-minute walk distance.73,81 Selexipag is an
Phosphodiesterase 5 Inhibitors oral selective prostacyclin receptor agonist that increases time to
Phosphodiesterase 5 inhibitors inhibit phosphodiesterase 5–based clinical worsening.70
degradation of cyclic guanosine monophosphate, causing vasodila-
tion, particularly in the pulmonary vasculature. In a randomized Monotherapy vs Combination Therapy
clinical trial of 278 patients with PAH, compared with placebo, Three large randomized trials demonstrated that initial treatment
sildenafil improved 6-minute walk distance by 45 m to 50 m, World with combination therapies improved clinical outcomes more than

jama.com (Reprinted) JAMA April 12, 2022 Volume 327, Number 14 1385

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 1386
Table 1. US Food and Drug Administration–Approved Medications for Group 1 Pulmonary Hypertensiona

Phosphodiesterase 5 inhibitors Endothelin receptor antagonists Prostacyclin analogues and prostacyclin receptor agonists
Guanylate cyclase
Sildenafil Tadalafil Bosentan Ambrisentan Macitentan stimulator: riociguat Epoprostenol Treprostinil Iloprost Selexipag
Mechanism of Enhances the Enhances the Binds to endothelin Binds to endothelin Binds to endothelin Enhances cGMP Mimics Mimics endogenous Mimics Selective
action nitric oxide–cGMP nitric receptors types A receptor type A and receptors types A production; acts as endogenous prostacyclin; potent endogenous prostacyclin
pathway and oxide–cGMP and B; blocks some type B; blocks and B; blocks a vasodilator prostacyclin; vasodilator, inhibits prostacyclin; receptor agonist;
slows cGMP pathway and endothelin- endothelin-mediated endothelin- potent platelet aggregation potent acts as a
degradation; acts slows cGMP mediated vasoconstriction mediated vasodilator, vasodilator, vasodilator and
as a pulmonary degradation; vasoconstriction vasoconstriction inhibits platelet inhibits platelet inhibits platelet
vasodilator acts as a aggregation aggregation aggregation
pulmonary
Clinical Review & Education Review

vasodilator
Common Headache Headache Increased hepatic Peripheral edema Anemia (13%), Hypotension Flushing Flushing (15%-45%), Flushing (27%), Flushing (12%),
adverse (16%-46%), (4%-42%), transaminases (14%-38%), headache (14%), (3%-10%), headache (23%-58%), headache headache (30%), headache (65%),
effects flushing flushing (about 12%; dose abnormal liver nasopharyngitis (27%), dizziness headache (27%-75%), diarrhea jaw pain (12%), diarrhea (42%),
(10%-19%), (2%-13%), dependent), edema function test results (20%), increased (20%), respiratory (46%-83%), (25%-69%), jaw pain cough (39%) jaw pain (26%)
dyspepsia nausea (11%), (11%), respiratory (<1%), anemia (7%), liver enzymes (>8× hemoptysis (1%), diarrhea (11%-18%), limb pain
(3%-17%), myalgia tract infections cough (13%) upper limit of epistaxis (37%-50%), jaw with all forms
epistaxis (1%-14%), (22%), fluid normal: 2%) pain (14%-18%); potential
(9%-13%), hypotension retention (≤3%) (54%-75%), line-associated

JAMA April 12, 2022 Volume 327, Number 14 (Reprinted)

hypotension (<2%) musculoskeletal complications with
(<2%) pain (3%-84%), intravenous form,
potential for infusion site pain with
line-associated subcutaneous form
complications (83%), cough with
inhaled form (54%)
Available Oral, intravenous Oral Oral Oral Oral Oral Continuous Continuous Inhaled via Oral
forms intravenous intravenous infusion, specialized
infusion continuous nebulizer
subcutaneous
infusion, inhaled via
specialized nebulizer
Notes Combination with Combination Teratogenic: Teratogenic: requires Teratogenic: Teratogenic: requires Avoid abrupt Avoid abrupt dose Avoid abrupt dose Avoid use in
riociguat with riociguat requires negative negative pregnancy requires negative negative pregnancy dose discontinuation or discontinuation severe hepatic
contraindicated contraindicated pregnancy test prior test prior to initiation pregnancy test prior testing prior to discontinuation dose reductions as or dose impairment

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

due to similar due to similar to initiation and and monthly during to initiation and initiation and or dose rebound pulmonary reductions as (Child-Pugh
mechanism of mechanism of monthly during use; use; evaluate liver monthly during use; monthly during use; reductions as hypertension may rebound Class C)
action; caution action; use not monthly monitoring enzymes and evaluate liver combination with rebound result; backup pulmonary
with use in kidney recommended of hepatic amino hemoglobin prior to enzymes and phosphodiesterase 5 pulmonary pump/device and hypertension may
failure in severe transaminases initiation of therapy, hemoglobin prior to inhibitors is hypertension medication are result; backup
hepatic required; avoid use at 1 mo, and as initiation of therapy, contraindicated due may result; necessary to avoid device and

© 2022 American Medical Association. All rights reserved.

impairment in moderate to needed during at 1 mo, and as to similar mechanism backup pump interruptions; use of medication are
(Child-Pugh severe hepatic therapy; avoid use in needed during of action; use not and medication oral form necessary to
Class C); caution impairment moderate to severe therapy; avoid use in recommended in are necessary to contraindicated in avoid
with use in (Child-Pugh hepatic impairment moderate to severe kidney failure or avoid severe hepatic interruptions
kidney failure Class B or C) (Child-Pugh hepatic impairment severe hepatic interruptions impairment
Class B or C) (Child-Pugh impairment (Child-Pugh Class C)
Class B or C) (Child-Pugh Class C)

Abbreviation: cGMP, cyclic guanosine monophosphate.

a
See Table 2 for efficacy data.

jama.com
Diagnosis and Treatment of Pulmonary Arterial Hypertension
 Table 2. Randomized Clinical Trials of Combination Therapy in PAH

Results

jama.com
Absolute data
Participants, PAH baseline Outcome
Source Trial name No. treatment Therapeutic group Comparator Duration Primary end point Intervention Comparator difference P value
Galiè et al,69 AMBITION 500 Nonea Ambrisentan and Ambrisentan or 24 wk Time to first event End-point event End-point event HR, 0.50 (95% CI, <.001
2015 tadalafil tadalafil of clinical failure occurred in 18% occurred in 31%b 0.35-0.72)
Humbert et al,82 BREATHE-2 33 Nonea Epoprostenol and Epoprostenol and 16 wk Total pulmonary Mean change, Mean change, .08
2004 bosentan placebo resistance −36.3% (SEM, −22.6% (SEM,
4.3%) 6.2%)
Hoeper et al,83 COMBI 40 Bosentan (100%) Inhaled iloprost Nonec 12 wk 6MWD Mean change, −9 m Mean change, −10 m .49
2006 (SD, 100 m) 1 m (SD, 27 m)
McLaughlin COMPASS-2 334 Sildenafil (100%) Bosentan Placebo 114 wkd Time to first event End-point event End-point event HR, 0.83 (95% CI, .25
et al,84 2015 of clinical failure occurred in 42.8% occurred in 0.58-1.19)
51.4%
Galiè et al,85 EARLY 185 None (84%); sildenafil Bosentan Placebo 26 wk PVR and 6MWD Geometric mean Geometric mean PVR: −22.6% (95% PVR:
2008 (16%) change in PVR: change in PVR: CI, −33.5% to <.001;
83.2%; mean 107.5%; mean −10.0%); 6MWD: 6MWD:
change in 6MWD: change in 6MWD: 19.1 m (95% CI, .08
Diagnosis and Treatment of Pulmonary Arterial Hypertension

11.2 m −7.9 m 3.6-41.8 m)

Tapson et al,86 FREEDOM-C 350 ERA (30%); PDE5 Oral treprostinil Placebo 16 wk 6MWD Median, 14.5 m Median, 4.8 m 11 m (95% CI, .07
2012 inhibitor (25%); ERA (IQR, −10 to (IQR, −22.0 to 0.0-22.0 m)
and PDE5 inhibitor 47.0 m) 35.5 m)
(45%)
Tapson et al,87 FREEDOM-C2 310 ERA (17%); PDE5 Oral treprostinil Placebo 16 wk 6MWD Median difference, .09
2013 inhibitor (43%); ERA 10.0 m (95% CI, −2
and PDE5 inhibitor to 22 m)
(40%)
White et al,73 FREEDOM-EV 690 PDE5 inhibitor or Oral treprostinil Placebo 60 wk Time to first event End-point event End-point event HR, 0.74 (95% CI, .28e
2020 soluble guanylate of clinical failure occurred in 26% occurred in 36% 0.56-0.97)
cyclase (72%); ERA
(28%)
Sitbon et al,70 GRIPHON 1156 None (20%); ERA Selexipag Placebo 70.7 wk Time to first event End-point event End-point event HR, 0.60 (95% CI, <.001e

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

2015 (15%); PDE5 inhibitor of clinical failure occurred in 27% occurred in 0.46-0.78)
(32%); ERA and PDE5 41.6%
inhibitor (33%)
Simonneau PACES 267 Intravenous Sildenafil Placebo 16 wk 6MWD Mean change, Mean change, 28.8 m (95% CI, <.001
et al,88 2008 epoprostenol (100%) 29.8 m 1.0 m 13.9-43.8 m)

© 2022 American Medical Association. All rights reserved.

Ghofrani et al,76 PATENT-1 443 None (50%); ERA Riociguat Placebo 12 wk 6MWD Mean change, 30 m Mean change, 36 m (95% CI, <.001e
2013 (44%); prostacyclin −6 m 20-52 m)
(6%)
Galiè et al,75 PHIRST 405 None (47%); bosentan Tadalafil Placebo 16 wk 6MWD 33 m (95% CI, <.01
2009 (53%) 15-50 m)f
Pulido et al,71 SERAPHIN 742 None (36%); PDE5 Macitentan Placebo 115 wk Time to first event End-point event End-point event HR, 0.55 (95% CI, <.001e
2013 inhibitor (61%); of clinical failure occurred in 31.4%g occurred in 0.39-0.76)g
oral/inhaled 46.4%
prostacyclin (5%)
McLaughlin STEP 67 Bosentan (100%) Inhaled iloprost Placebo 12 wk 6MWD Mean change, 30 m Mean change, 26 m .051
et al,89 2006 4m

(continued)

(Reprinted) JAMA April 12, 2022 Volume 327, Number 14

Review Clinical Review & Education

1387
 Clinical Review & Education Review Diagnosis and Treatment of Pulmonary Arterial Hypertension

initial therapy with a single drug69-71 (Table 2). Combination pulmo-

nary vasodilator therapy consists of either simultaneous initiation

P value

<.001

<.05

Results for subgroup of patients receiving background therapy consistent with the overall study findings.
.42
of treatment with multiple therapies or sequential addition over sev-
eral weeks of an additional agent or agents to a single agent initi-

Ratio of geometric
ated at baseline.

20.0 m (95% CI,

means, 0.096
In a clinical trial of 500 participants randomized to receive either

8.0-32.8 m)
0.86-1.07)h
difference
Outcome

ambrisentan combined with tadalafil, ambrisentan alone, or tada-

(95% CI, lafil alone, combination therapy decreased rates of a composite end
point of death, hospitalization for worsening PAH, disease progres-
(IQR, −26.0 to sion, or unsatisfactory long-term clinical response, compared with
Change, −52%

Median, 3.0 m

Mean change,
monotherapy with either agent (hazard ratio for the combination
Comparator

Mean placebo-adjusted treatment difference for 40-mg tadalafil dose.

group vs the pooled monotherapy group, 0.5; 95% CI, 0.35-0.72;
31.5 m)

18.3 m
P < .001 [absolute rate data were not included in the published ar-
ticle]), in addition to statistically significant improvements in 6-min-
ute walk distance and NT-proBNP.69
Median, 21.6 m
Change, −54%

In a clinical trial of 1156 patients with PAH who were randomized

Mean change,
Absolute data

(IQR, −8.0 to
Intervention

to receive placebo or selexipag, selexipag reduced clinical failure

Data presented as available from primary study.
54.0 m)
Results

54.4 m

events, defined as death from any cause or a complication related to

PAH, compared with placebo (hazard ratio, 0.60; 99% CI, 0.46-
0.78; P < .001 [absolute rate data were not included in the published
Duration Primary end point

article]).70 Nearly 47% of patients were receiving background PAH-

For 10-mg macitentan dose.

specific monotherapy (15% with an endothelin receptor antagonist;

32% with a phosphodiesterase 5 inhibitor) and 33% were receiving
6MWD

6MWD
PVR

dual therapy (combination of an endothelin receptor antagonist and

a phosphodiesterase 5 inhibitor).70 Prespecified subgroup analysis
found that the effect of selexipag was similar in the subgroup of pa-
26 wk

12 wk

16 wk

tients who were already receiving treatment at baseline.70

In a clinical trial of 742 participants, in which 66.8% were tak-
h

ing a background phosphodiesterase 5 inhibitor or oral or inhaled

g
e
Macitentan and

f
Comparator

prostacyclin, macitentan decreased rates of clinical failure events,

tadalafil

Inhaled treprostinil Placebo

Placebo

defined as death, atrial septostomy, lung transplant, initiation of

treatment with intravenous or subcutaneous prostanoids, or wors-
PAH, pulmonary arterial hypertension; PDE5, phosphodiesterase 5; PVR, pulmonary vascular resistance.

ening of PAH, compared with placebo (hazard ratio, 0.55; 97.5% CI,
Abbreviations: ERA, endothelin receptor antagonist; HR, hazard ratio; 6MWD, 6-minute walk distance;
Therapeutic group

0.39-0.76; P < .001 [absolute rate data were not included in the pub-
lished article]).71 In the background therapy subgroup, the risk of the
tadalafil, and
Macitentan,

selexipag

composite primary end point was reduced by 38% (P = .009) com-

Tadalafil

pared with placebo.71,93

Table 2. Randomized Clinical Trials of Combination Therapy in PAH (continued)

In sum, several large randomized clinical trials and a subse-

quent meta-analysis (n = 4095; relative risk, 0.65; 95% CI, 0.58-
Ambrisentan (100%)

0.72; P < .001 [absolute rate data were not included in the pub-
Bosentan (70%);
sildenafil (30%)

lished article]) support combination therapy as first-line therapy in

PAH baseline

PAH over monotherapy.72 However, it remains unclear whether the

treatment

Patients received bosentan and inhaled iloprost or bosentan only.

Nonea

efficacy findings from these trials can be generalized to their respec-

tive drug classes or to only the specific drugs, or combination, tested.
Initial combination therapy in treatment-naive patients.

Although they are all endothelin receptor antagonist/phosphodi-

Participants,

esterase 5 inhibitor combinations, ambrisentan and tadalafil as well

as macitentan and a phosphodiesterase 5 inhibitor in combination
247

235

124
No.

have shown efficacy in a randomized clinical trial, but the combina-

tion of bosentan and sildenafil were not efficacious in a random-
Mean bosentan treatment duration.

ized clinical trial.69,71,84 This concept extends not only to individual

Trial name

drug selection but also to the number of drugs used in combina-

TRIUMPH
TRITON

tion. For example, a clinical trial of 247 treatment-naive patients with

Pooled monotherapy.

PAH randomized to initial 2-drug therapy with macitentan and tada-

lafil vs 3-drug therapy with macitentan, tadalafil, and selexipag re-
Zhuang et al,92
et al,91 2010

ported no statistically significant difference in pulmonary vascular

Chin et al,90

McLaughlin

resistance at 26 weeks between groups (decreased by 52% and 54%,

Source

2021

2014

respectively; P = .42), further underscoring the need for efficacy test-

ing of individual regimens.90
b

d
a

1388 JAMA April 12, 2022 Volume 327, Number 14 (Reprinted) jama.com

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Diagnosis and Treatment of Pulmonary Arterial Hypertension Review Clinical Review & Education

Some subgroups of PAH are not well represented in combina- sterone antagonists such as spironolactone can be initiated for neu-
tion therapy clinical trials (eg, portopulmonary hypertension), and rohormonal blockade or renin-angiotensin-aldosterone modula-
the efficacy of monotherapy vs combination therapy in these sub- tion, diuresis, and prevention of hypokalemia.95
groups remains unclear. Although no PAH-specific evidence exists regarding the ben-
efit of oxygen therapy, oxygen is recommended when PaO2 is con-
Initiation of Guideline-Based Therapy sistently less than 60 mm Hg, following guidelines for chronic ob-
Practice guidelines recommend that patients who have not received structive pulmonary disease.96 Patients may require additional
prior therapy for PAH who are at low to intermediate risk of death supplemental oxygen for travel by air or to high altitudes due to the
by risk assessment and do not meet criteria for vasoreactivity should risk of hypoxemia.
start oral combination therapy.4,40,94 Oral combinations of ambrisen- In premenopausal women, birth control counseling is critical be-
tan and tadalafil, macitentan added sequentially to a phosphodies- cause pregnant patients with PAH are at high risk of right ventricu-
terase 5 inhibitor, selexipag added sequentially to a phosphodiester- lar failure and death as a result of pregnancy-related changes in car-
ase 5 inhibitor and/or an endothelin receptor antagonist, or oral diac output and volume.97 Maternal mortality can be 13% to 16.7%
treprostinil added sequentially to a phosphodiesterase 5 inhibitor, in patients with PAH who continue pregnancy. 98 Estrogen-
soluble guanylate cyclase stimulator, and/or endothelin receptor an- containing contraception should be avoided due to the increased
tagonist have been found to be efficacious compared with placebo risk of thromboembolism.99
and/or monotherapy.69-71,73 If low-risk status according to a risk cal-
culator is not achieved within 3 to 6 months, the addition of a pros-
tacyclin analogue is recommended.4,40,94 Combination therapy, in-
Limitations
cluding an intravenous prostacyclin, is recommended for patients ini-
tially classified as high-risk by a risk calculator.4,40,94 Monotherapy This review has several limitations. First, the quality of the evi-
can be considered in very low-risk populations or in patients who have dence is limited by the quality of the published studies on PAH.
been stable with monotherapy for more than 1 to 2 years.4 Second, it is possible that some relevant articles have been
Progressively titrated high-dose calcium channel blockers are missed. Third, a formal quality assessment of the included articles
the treatment of choice for the subset of patients who are candi- was not performed.
dates for and meet criteria for vasoreactivity, defined as demon-
strating acute vasodilation of the pulmonary vasculature in re-
sponse to inhaled nitric oxide challenge.4,40,49 Calcium channel
Conclusions
blockers may cause hypotension and syncope in patients who do not
meet criteria for vasoreactivity.40 Pulmonary arterial hypertension affects 10.6 per 1 million adults
in the US and without treatment typically progresses to right
Adjunctive Therapy heart failure and death. First-line therapy with drug combinations
Standard diuretics are a mainstay of PAH therapy in patients with that target multiple biological pathways are associated with
clinical signs of right ventricular failure and volume overload. Aldo- improved survival.

ARTICLE INFORMATION 2. Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of 8. Stacher E, Graham BB, Hunt JM, et al. Modern
Accepted for Publication: March 9, 2022. pulmonary hypertension. Eur Respir J. 2019;53(1): age pathology of pulmonary arterial hypertension.
1801904. doi:10.1183/13993003.01904-2018 Am J Respir Crit Care Med. 2012;186(3):261-272. doi:
Author Contributions: Drs Ruopp and Cockrill had 10.1164/rccm.201201-0164OC
full access to all of the data in the study and take 3. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in
responsibility for the integrity of the data and the patients with primary pulmonary hypertension: 9. Tuder RM. Pulmonary vascular remodeling in
accuracy of the data analysis. results from a national prospective registry. Ann pulmonary hypertension. Cell Tissue Res. 2017;367
Concept and design: Both authors. Intern Med. 1991;115(5):343-349. doi:10.7326/ (3):643-649. doi:10.1007/s00441-016-2539-y
Acquisition, analysis, or interpretation of data: Both 0003-4819-115-5-343 10. Sun XG, Hansen JE, Oudiz RJ, Wasserman K.
authors. 4. Galiè N, Channick RN, Frantz RP, et al. Risk Pulmonary function in primary pulmonary
Drafting of the manuscript: Both authors. stratification and medical therapy of pulmonary hypertension. J Am Coll Cardiol. 2003;41(6):1028-
Critical revision of the manuscript for important arterial hypertension. Eur Respir J. 2019;53(1): 1035. doi:10.1016/S0735-1097(02)02964-9
intellectual content: Both authors. 1801889. doi:10.1183/13993003.01889-2018 11. Vonk Noordegraaf A, Chin KM, Haddad F, et al.
Administrative, technical, or material support: 5. Simonneau G, Montani D, Celermajer DS, et al. Pathophysiology of the right ventricle and of the
Ruopp. Haemodynamic definitions and updated clinical pulmonary circulation in pulmonary hypertension:
Conflict of Interest Disclosures: None reported. classification of pulmonary hypertension. Eur Respir an update. Eur Respir J. 2019;53(1):1801900. doi:10.
Submissions: We encourage authors to submit J. 2019;53(1):1801913. doi:10.1183/13993003. 1183/13993003.01900-2018
papers for consideration as a Review. Please 01913-2018 12. Humbert M, Sitbon O, Chaouat A, et al.
contact Mary McGrae McDermott, MD, at 6. Maron BA, Hess E, Maddox TM, et al. Pulmonary arterial hypertension in France: results
mdm608@northwestern.edu. Association of borderline pulmonary hypertension from a national registry. Am J Respir Crit Care Med.
with mortality and hospitalization in a large patient 2006;173(9):1023-1030. doi:10.1164/rccm.200510-
REFERENCES cohort: insights from the Veterans Affairs Clinical 1668OC
1. Badesch DB, Raskob GE, Elliott CG, et al. Assessment, Reporting, and Tracking program. 13. Rich S, Dantzker DR, Ayres SM, et al. Primary
Pulmonary arterial hypertension: baseline Circulation. 2016;133(13):1240-1248. doi:10.1161/ pulmonary hypertension: a national prospective
characteristics from the REVEAL registry. Chest. CIRCULATIONAHA.115.020207 study. Ann Intern Med. 1987;107(2):216-223. doi:10.
2010;137(2):376-387. doi:10.1378/chest.09-1140 7. Kim D, George MP. Pulmonary hypertension. 7326/0003-4819-107-2-216
Med Clin North Am. 2019;103(3):413-423. doi:10.
1016/j.mcna.2018.12.002

jama.com (Reprinted) JAMA April 12, 2022 Volume 327, Number 14 1389

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Clinical Review & Education Review Diagnosis and Treatment of Pulmonary Arterial Hypertension

14. McGoon MD, Benza RL, Escribano-Subias P, 29. Chung L, Liu J, Parsons L, et al. 43. Graham BB, Bandeira AP, Morrell NW, et al.
et al. Pulmonary arterial hypertension: Characterization of connective tissue Schistosomiasis-associated pulmonary
epidemiology and registries. J Am Coll Cardiol. 2013; disease-associated pulmonary arterial hypertension hypertension: pulmonary vascular disease: the
62(25)(suppl):D51-D59. doi:10.1016/j.jacc.2013.10. from REVEAL: identifying systemic sclerosis as a global perspective. Chest. 2010;137(6)(suppl):20S-
023 unique phenotype. Chest. 2010;138(6):1383-1394. 29S. doi:10.1378/chest.10-0048
15. Farber HW, Miller DP, Poms AD, et al. Five-year doi:10.1378/chest.10-0260 44. Sibomana JP, Campeche A, Carvalho-Filho RJ,
outcomes of patients enrolled in the REVEAL 30. Hachulla E, Carpentier P, Gressin V, et al. Risk et al. Schistosomiasis pulmonary arterial
registry. Chest. 2015;148(4):1043-1054. doi:10. factors for death and the 3-year survival of patients hypertension. Front Immunol. 2020;11:608883.
1378/chest.15-0300 with systemic sclerosis: the French doi:10.3389/fimmu.2020.608883
16. Boucly A, Savale L, Jaïs X, et al. Association ItinérAIR-Sclérodermie study. Rheumatology (Oxford). 45. Mickael CS, Graham BB. The role of type 2
between initial treatment strategy and long-term 2009;48(3):304-308. doi:10.1093/rheumatology/ inflammation in Schistosoma-induced pulmonary
survival in pulmonary arterial hypertension. Am J ken488 hypertension. Front Immunol. 2019;10:27. doi:10.
Respir Crit Care Med. 2021;204(7):842-854. doi:10. 31. Naranjo M, Hassoun PM. Systemic 3389/fimmu.2019.00027
1164/rccm.202009-3698OC sclerosis-associated pulmonary hypertension: 46. Masi B, Perles-Barbacaru TA, Bernard M,
17. Loyd JE, Primm RK, Newman JH. Familial spectrum and impact. Diagnostics (Basel). 2021;11 Viola A. Clinical and preclinical imaging of
primary pulmonary hypertension: clinical patterns. (5):911. doi:10.3390/diagnostics11050911 hepatosplenic schistosomiasis. Trends Parasitol.
Am Rev Respir Dis. 1984;129(1):194-197. 32. Coghlan JG, Denton CP, Grünig E, et al. 2020;36(2):206-226. doi:10.1016/j.pt.2019.11.007
18. Machado RD, Eickelberg O, Elliott CG, et al. Evidence-based detection of pulmonary arterial 47. Sitbon O, Humbert M, Jaïs X, et al. Long-term
Genetics and genomics of pulmonary arterial hypertension in systemic sclerosis: the DETECT response to calcium channel blockers in idiopathic
hypertension. J Am Coll Cardiol. 2009;54(1)(suppl): study. Ann Rheum Dis. 2014;73(7):1340-1349. doi: pulmonary arterial hypertension. Circulation. 2005;
S32-S42. doi:10.1016/j.jacc.2009.04.015 10.1136/annrheumdis-2013-203301 111(23):3105-3111. doi:10.1161/CIRCULATIONAHA.104.
19. Morrell NW, Aldred MA, Chung WK, et al. 33. Sitbon O, Lascoux-Combe C, Delfraissy J-F, 488486
Genetics and genomics of pulmonary arterial et al. Prevalence of HIV-related pulmonary arterial 48. Hemnes AR, Zhao M, West J, et al. Critical
hypertension. Eur Respir J. 2019;53(1):1801899. doi: hypertension in the current antiretroviral therapy genomic networks and vasoreactive variants in
10.1183/13993003.01899-2018 era. Am J Respir Crit Care Med. 2008;177(1):108-113. idiopathic pulmonary arterial hypertension. Am J
doi:10.1164/rccm.200704-541OC Respir Crit Care Med. 2016;194(4):464-475. doi:10.
20. Harrison RE, Flanagan JA, Sankelo M, et al.
Molecular and functional analysis identifies ALK-1 as 34. Le Pavec J, Souza R, Herve P, et al. 1164/rccm.201508-1678OC
the predominant cause of pulmonary hypertension Portopulmonary hypertension: survival and 49. Rich S, Kaufmann E, Levy PS. The effect of high
related to hereditary haemorrhagic telangiectasia. prognostic factors. Am J Respir Crit Care Med. doses of calcium-channel blockers on survival in
J Med Genet. 2003;40(12):865-871. doi:10.1136/ 2008;178(6):637-643. doi:10.1164/rccm.200804- primary pulmonary hypertension. N Engl J Med.
jmg.40.12.865 613OC 1992;327(2):76-81. doi:10.1056/
21. Sztrymf B, Coulet F, Girerd B, et al. Clinical 35. Krowka MJ, Swanson KL, Frantz RP, McGoon NEJM199207093270203
outcomes of pulmonary arterial hypertension in MD, Wiesner RH. Portopulmonary hypertension: 50. Lantuéjoul S, Sheppard MN, Corrin B, et al.
carriers of BMPR2 mutation. Am J Respir Crit Care results from a 10-year screening algorithm. Pulmonary veno-occlusive disease and pulmonary
Med. 2008;177(12):1377-1383. doi:10.1164/rccm. Hepatology. 2006;44(6):1502-1510. doi:10.1002/hep. capillary hemangiomatosis. Am J Surg Pathol.
200712-1807OC 21431 2006;30(7):850-857. doi:10.1097/01.pas.
22. Girerd B, Montani D, Coulet F, et al. Clinical 36. Krowka MJ. Portopulmonary hypertension. 0000209834.69972.e5
outcomes of pulmonary arterial hypertension in Semin Respir Crit Care Med. 2012;33(1):17-25. doi: 51. Montani D, Achouh L, Dorfmüller P, et al.
patients carrying an ACVRL1 (ALK1) mutation. Am J 10.1055/s-0032-1301731 Pulmonary veno-occlusive disease: clinical,
Respir Crit Care Med. 2010;181(8):851-861. doi:10. 37. Al-Naamani N, Krowka MJ, Forde KA, et al. functional, radiologic, and hemodynamic
1164/rccm.200908-1284OC Estrogen signaling and portopulmonary characteristics and outcome of 24 cases confirmed
23. Zamanian RT, Hedlin H, Greuenwald P, et al. hypertension: the Pulmonary Vascular by histology. Medicine (Baltimore). 2008;87(4):
Features and outcomes of methamphetamine- Complications of Liver Disease Study (PVCLD2). 220-233. doi:10.1097/MD.0b013e31818193bb
associated pulmonary arterial hypertension. Am J Hepatology. 2021;73(2):726-737. doi:10.1002/hep. 52. Palmer SM, Robinson LJ, Wang A, et al. Massive
Respir Crit Care Med. 2018;197(6):788-800. doi:10. 31314 pulmonary edema and death after prostacyclin
1164/rccm.201705-0943OC 38. Martin P, DiMartini A, Feng S, et al. Evaluation infusion in a patient with pulmonary veno-occlusive
24. Hachulla E, Gressin V, Guillevin L, et al. Early for liver transplantation in adults: 2013 practice disease. Chest. 1998;113(1):237-240. doi:10.1378/
detection of pulmonary arterial hypertension in guideline by the American Association for the Study chest.113.1.237
systemic sclerosis. Arthritis Rheum. 2005;52(12): of Liver Diseases and the American Society of 53. Best DH, Sumner KL, Austin ED, et al. EIF2AK4
3792-3800. doi:10.1002/art.21433 Transplantation. Hepatology. 2014;59(3):1144-1165. mutations in pulmonary capillary hemangiomatosis.
doi:10.1002/hep.26972 Chest. 2014;145(2):231-236. doi:10.1378/chest.13-
25. Montani D, Bergot E, Günther S, et al.
Pulmonary arterial hypertension in patients treated 39. Savale L, Sattler C, Coilly A, et al. Long-term 2366
by dasatinib. Circulation. 2012;125(17):2128-2137. outcome in liver transplantation candidates with 54. Mandell E, Kinsella JP, Abman SH. Persistent
doi:10.1161/CIRCULATIONAHA.111.079921 portopulmonary hypertension. Hepatology. 2017; pulmonary hypertension of the newborn. Pediatr
65(5):1683-1692. doi:10.1002/hep.28990 Pulmonol. 2021;56(3):661-669. doi:10.1002/ppul.
26. Weatherald J, Chaumais M-C, Savale L, et al.
Long-term outcomes of dasatinib-induced 40. Galiè N, Humbert M, Vachiery JL, et al. 2015 25073
pulmonary arterial hypertension. Eur Respir J. 2017; ESC/ERS guidelines for the diagnosis and treatment 55. Steurer MA, Jelliffe-Pawlowski LL, et al.
50(1):1700217. doi:10.1183/13993003.00217-2017 of pulmonary hypertension. Eur Heart J. 2016;37 Persistent pulmonary hypertension of the newborn
(1):67-119. doi:10.1093/eurheartj/ehv317 in late preterm and term infants in California.
27. Shah NP, Wallis N, Farber HW, et al. Clinical
features of pulmonary arterial hypertension in 41. Manes A, Palazzini M, Leci E, et al. Current era Pediatrics. 2017;139(1):e20161165. doi:10.1542/peds.
patients receiving dasatinib. Am J Hematol. 2015; survival of patients with pulmonary arterial 2016-1165
90(11):1060-1064. doi:10.1002/ajh.24174 hypertension associated with congenital heart 56. Brown LM, Chen H, Halpern S, et al. Delay in
disease. Eur Heart J. 2014;35(11):716-724. doi:10. recognition of pulmonary arterial hypertension:
28. Mukerjee D, St George D, Coleiro B, et al. 1093/eurheartj/eht072
Prevalence and outcome in systemic sclerosis factors identified from the REVEAL registry. Chest.
associated pulmonary arterial hypertension: 42. Hopkins WE. The remarkable right ventricle of 2011;140(1):19-26. doi:10.1378/chest.10-1166
application of a registry approach. Ann Rheum Dis. patients with Eisenmenger syndrome. Coron Artery 57. Wertheim BM, Cockrill BA. Evaluation for the
2003;62(11):1088-1093. doi:10.1136/ard.62.11.1088 Dis. 2005;16(1):19-25. doi:10.1097/00019501- dyspneic patient in primary care. In: Singh AK,
200502000-00004 Loscalzo J, eds. Brigham Intensive Review of
Internal Medicine. 3rd ed. Elsevier; 2017: 339-347.

1390 JAMA April 12, 2022 Volume 327, Number 14 (Reprinted) jama.com

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022

 Diagnosis and Treatment of Pulmonary Arterial Hypertension Review Clinical Review & Education

58. Ahearn GS, Tapson VF, Rebeiz A, Greenfield JC Jr. pulmonary arterial hypertension. Lancet Respir Med. hypertension in patients on background endothelin
Electrocardiography to define clinical status in 2016;4(4):291-305. doi:10.1016/S2213-2600(16) receptor antagonist and/or phosphodiesterase type
primary pulmonary hypertension and pulmonary 00027-8 5 inhibitor therapy (the FREEDOM-C study). Chest.
arterial hypertension secondary to collagen vascular 73. White RJ, Jerjes-Sanchez C, Bohns Meyer GM, 2012;142(6):1383-1390. doi:10.1378/chest.11-2212
disease. Chest. 2002;122(2):524-527. doi:10.1378/ et al. Combination therapy with oral treprostinil for 87. Tapson VF, Jing ZC, Xu KF, et al. Oral
chest.122.2.524 pulmonary arterial hypertension. Am J Respir Crit treprostinil for the treatment of pulmonary arterial
59. Bonderman D, Wexberg P, Martischnig AM, Care Med. 2020;201(6):707-717. doi:10.1164/rccm. hypertension in patients receiving background
et al. A noninvasive algorithm to exclude 201908-1640OC endothelin receptor antagonist and
pre-capillary pulmonary hypertension. Eur Respir J. 74. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil phosphodiesterase type 5 inhibitor therapy (the
2011;37(5):1096-1103. doi:10.1183/09031936. citrate therapy for pulmonary arterial hypertension. FREEDOM-C2 study). Chest. 2013;144(3):952-958.
00089610 N Engl J Med. 2005;353(20):2148-2157. doi:10. doi:10.1378/chest.12-2875
60. Simpson CE, Damico RL, Hassoun PM, et al. 1056/NEJMoa050010 88. Simonneau G, Rubin LJ, Galiè N, et al. Addition
Noninvasive prognostic biomarkers for left-sided 75. Galiè N, Brundage BH, Ghofrani HA, et al. of sildenafil to long-term intravenous epoprostenol
heart failure as predictors of survival in pulmonary Tadalafil therapy for pulmonary arterial therapy in patients with pulmonary arterial
arterial hypertension. Chest. 2020;157(6):1606-1616. hypertension. Circulation. 2009;119(22):2894-2903. hypertension. Ann Intern Med. 2008;149(8):521-530.
doi:10.1016/j.chest.2019.12.037 doi:10.1161/CIRCULATIONAHA.108.839274 doi:10.7326/0003-4819-149-8-200810210-
61. Ullah W, Minalyan A, Saleem S, et al. 00004
76. Ghofrani HA, Galiè N, Grimminger F, et al.
Comparative accuracy of non-invasive imaging Riociguat for the treatment of pulmonary arterial 89. McLaughlin VV, Oudiz RJ, Frost A, et al.
versus right heart catheterization for the diagnosis hypertension. N Engl J Med. 2013;369(4):330-340. Randomized study of adding inhaled iloprost to
of pulmonary hypertension. Int J Cardiol Heart Vasc. doi:10.1056/NEJMoa1209655 existing bosentan in pulmonary arterial
2020;29:100568. doi:10.1016/j.ijcha.2020.100568 hypertension. Am J Respir Crit Care Med. 2006;174
77. Galiè N, Muller K, Scalise AV, Grunig E. PATENT (11):1257-1263. doi:10.1164/rccm.200603-358OC
62. Ni JR, Yan PJ, Liu SD, et al. Diagnostic accuracy PLUS: a blinded, randomised and extension study
of transthoracic echocardiography for pulmonary of riociguat plus sildenafil in pulmonary arterial 90. Chin KM, Sitbon O, Doelberg M, et al. Three-
hypertension. BMJ Open. 2019;9(12):e033084. doi: hypertension. Eur Respir J. 2015;45:1314-1322. doi: versus two-drug therapy for patients with newly
10.1136/bmjopen-2019-033084 10.1183/09031936.00105914 diagnosed pulmonary arterial hypertension. J Am
63. Amsallem M, Sternbach JM, Adigopula S, et al. Coll Cardiol. 2021;78(14):1393-1403. doi:10.1016/j.
78. Channick RN, Simonneau G, Sitbon O, et al. jacc.2021.07.057
Addressing the controversy of estimating Effects of the dual endothelin-receptor antagonist
pulmonary arterial pressure by echocardiography. bosentan in patients with pulmonary hypertension. 91. McLaughlin VV, Benza RL, Rubin LJ, et al.
J Am Soc Echocardiogr. 2016;29(2):93-102. doi:10. Lancet. 2001;358(9288):1119-1123. doi:10.1016/ Addition of inhaled treprostinil to oral therapy for
1016/j.echo.2015.11.001 S0140-6736(01)06250-X pulmonary arterial hypertension. J Am Coll Cardiol.
64. Farber HW, Foreman AJ, Miller DP, 2010;55(18):1915-1922. doi:10.1016/j.jacc.2010.01.027
79. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan
McGoon MD. REVEAL registry: correlation of therapy for pulmonary arterial hypertension. N Engl 92. Zhuang Y, Jiang B, Gao H, Zhao W. Randomized
right heart catheterization and echocardiography in J Med. 2002;346(12):896-903. doi:10.1056/ study of adding tadalafil to existing ambrisentan in
patients with pulmonary arterial hypertension. NEJMoa012212 pulmonary arterial hypertension. Hypertens Res.
Congest Heart Fail. 2011;17(2):56-64. doi:10.1111/j. 2014;37(6):507-512. doi:10.1038/hr.2014.28
1751-7133.2010.00202.x 80. Barst RJ, Rubin LJ, Long WA, et al.
A comparison of continuous intravenous 93. Sitbon O, Gaine S. Beyond a single pathway:
65. O’Leary JM, Assad TR, Xu M, et al. Lack of epoprostenol (prostacyclin) with conventional combination therapy in pulmonary arterial
a tricuspid regurgitation Doppler signal and therapy for primary pulmonary hypertension. hypertension. Eur Respir Rev. 2016;25(142):408-417.
pulmonary hypertension by invasive measurement. N Engl J Med. 1996;334(5):296-301. doi:10.1056/ doi:10.1183/16000617.0085-2016
J Am Heart Assoc. 2018;7(13):e009362. doi:10. NEJM199602013340504 94. Klinger JR, Elliott CG, Levine DJ, et al. Therapy
1161/JAHA.118.009362 for pulmonary arterial hypertension in adults:
81. Simonneau G, Barst RJ, Galiè N, et al.
66. Trip P, Nossent EJ, de Man FS, et al. Severely Continuous subcutaneous infusion of treprostinil, update of the CHEST guideline and expert panel
reduced diffusion capacity in idiopathic pulmonary a prostacyclin analogue, in patients with pulmonary report. Chest. 2019;155(3):565-586. doi:10.1016/j.
arterial hypertension. Eur Respir J. 2013;42(6):1575- arterial hypertension. Am J Respir Crit Care Med. chest.2018.11.030
1585. doi:10.1183/09031936.00184412 2002;165(6):800-804. doi:10.1164/ajrccm.165.6. 95. Maron BA, Leopold JA, Hemnes AR. Metabolic
67. Pi H, Kosanovich CM, Handen A, et al. 2106079 syndrome, neurohumoral modulation, and
Outcomes of pulmonary arterial hypertension are 82. Humbert M, Barst RJ, Robbins IM, et al. pulmonary arterial hypertension. Br J Pharmacol.
improved in a specialty care center. Chest. 2020; Combination of bosentan with epoprostenol in 2020;177(7):1457-1471. doi:10.1111/bph.14968
158(1):330-340. doi:10.1016/j.chest.2020.01.046 pulmonary arterial hypertension: BREATHE-2. Eur 96. Weitzenblum E, Sautegeau A, Ehrhart M, et al.
68. Hoeper MM, Lee SH, Voswinckel R, et al. Respir J. 2004;24(3):353-359. doi:10.1183/ Long-term oxygen therapy can reverse the
Complications of right heart catheterization 09031936.04.00028404 progression of pulmonary hypertension in patients
procedures in patients with pulmonary 83. Hoeper MM, Leuchte H, Halank M, et al. with chronic obstructive pulmonary disease. Am
hypertension in experienced centers. J Am Coll Combining inhaled iloprost with bosentan in Rev Respir Dis. 1985;131(4):493-498. doi:10.1164/
Cardiol. 2006;48(12):2546-2552. doi:10.1016/j.jacc. patients with idiopathic pulmonary arterial arrd.1985.131.4.493
2006.07.061 hypertension. Eur Respir J. 2006;28(4):691-694. 97. Hemnes AR, Kiely DG, Cockrill BA, et al.
69. Galiè N, Barberà JA, Frost AE, et al. Initial use of doi:10.1183/09031936.06.00057906 Statement on pregnancy in pulmonary
ambrisentan plus tadalafil in pulmonary arterial 84. McLaughlin V, Channick RN, Ghofrani HA, et al. hypertension from the Pulmonary Vascular
hypertension. N Engl J Med. 2015;373(9):834-844. Bosentan added to sildenafil therapy in patients Research Institute. Pulm Circ. 2015;5(3):435-465.
doi:10.1056/NEJMoa1413687 with pulmonary arterial hypertension. Eur Respir J. doi:10.1086/682230
70. Sitbon O, Channick R, Chin KM, et al. Selexipag 2015;46(2):405-413. doi:10.1183/13993003.02044- 98. Jaïs X, Olsson KM, Barbera JA, et al. Pregnancy
for the treatment of pulmonary arterial 2014 outcomes in pulmonary arterial hypertension in the
hypertension. N Engl J Med. 2015;373(26):2522-2533. 85. Galiè N, Rubin Lj, Hoeper M, et al. Treatment of modern management era. Eur Respir J. 2012;40
doi:10.1056/NEJMoa1503184 patients with mildly symptomatic pulmonary (4):881-885. doi:10.1183/09031936.00141211
71. Pulido T, Adzerikho I, Channick RN, et al. arterial hypertension with bosentan (EARLY study). 99. Fessel JP, Chen X, Frump A, et al. Interaction
Macitentan and morbidity and mortality in Lancet. 2008;371(9630):2093-2100. doi:10.1016/ between bone morphogenetic protein receptor
pulmonary arterial hypertension. N Engl J Med. S0140-6736(08)60919-8 type 2 and estrogenic compounds in pulmonary
2013;369(9):809-818. doi:10.1056/NEJMoa1213917 86. Tapson VF, Torres F, Kermeen F, et al. Oral arterial hypertension. Pulm Circ. 2013;3(3):564-577.
72. Lajoie AC, Lauzière G, Lega JC, et al. treprostinil for the treatment of pulmonary arterial doi:10.1086/674312
Combination therapy versus monotherapy for

jama.com (Reprinted) JAMA April 12, 2022 Volume 327, Number 14 1391

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a FLENI - Fundacion para la Luch User on 04/13/2022