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Review Article
P
ulmonary hypertension is a syndrome characterized by marked From the Division of Pulmonary and Crit-
remodeling of the pulmonary vasculature and a progressive rise in the pul- ical Care Medicine, Department of Medi-
cine, Johns Hopkins University School of
monary vascular load, leading to hypertrophy and remodeling of the right Medicine, Baltimore. Dr. Hassoun can be
ventricle. Death results from right ventricular failure if pulmonary hypertension is contacted at phassoun@jhmi.edu or at
left untreated. Pulmonary hypertension is currently defined hemodynamically by the Division of Pulmonary and Critical
Care Medicine, Johns Hopkins University
a mean pulmonary arterial pressure of higher than 20 mm Hg at rest, as measured School of Medicine, 1830 E. Monument
by right heart catheterization.1 Precapillary pulmonary hypertension due to pulmo- St., Baltimore, MD 21287.
nary vascular disease is further defined by an elevation in pulmonary vascular N Engl J Med 2021;385:2361-76.
resistance of at least 3 Wood units (WU), in contrast to isolated postcapillary DOI: 10.1056/NEJMra2000348
pulmonary hypertension, in which the pulmonary vascular resistance is less than Copyright © 2021 Massachusetts Medical Society.
3 WU and the elevation in the mean pulmonary arterial pressure is due to elevated CME
filling pressures on the left side of the heart. at NEJM.org
The several forms of pulmonary hypertension are categorized into five clinical
groups (Fig. 1). This review focuses on the relatively rare form of pulmonary arte-
rial hypertension (group 1). Immense progress has been achieved in gaining an
understanding of the mechanisms, natural history, and genetic features of pulmo-
nary arterial hypertension and in establishing targeted therapy. A full appreciation
of the pathophysiology of the syndrome is important, since the diagnosis requires
a thorough clinical investigation to rule out other, more common forms of pulmo-
nary hypertension, for which treatment of the underlying disease should be the
primary goal.
The first anatomical description of pulmonary hypertension is credited to von
Romberg.2 However, it is the advent of human right heart catheterization, first
performed by Forssmann on himself in 1929,3 that led to a flurry of physiological
observations on the heart and pulmonary circulation by Cournand and Richards
in the 1940s. The three investigators received the Nobel Prize in Physiology or
Medicine in 1956 for their seminal work. In his illuminating Nobel Lecture, Richards
noted that, as a result of their collective work, “many forms and degrees of failure
were defined, and their responses to treatment measured.”4
In 1951, Dresdale, a disciple of Cournand and Richards, and colleagues pre-
sented the first case series of patients with pulmonary hypertension of unknown
cause, defined as “primary pulmonary hypertension.”5 Greater awareness of the
disease developed in the 1960s, after an epidemic of primary pulmonary hyperten-
sion that was associated with the use of the appetite suppressant aminorex.6 This
prompted the World Health Organization to convene a first meeting of pulmonary
hypertension experts in 1973, to standardize the clinical and pathological nomen-
clature of primary pulmonary hypertension, the first attempt at an organized
classification.7 The first and second meetings about pulmonary hypertension were
separated by 25 years, but thereafter the World Symposium on Pulmonary Hyper-
tension (WSPH) was convened every 5 years. The meetings brought further refine-
ment to the classification of pulmonary hypertension, with five distinct groups
1 PAH
Subcategory Clinical characteristics
1.1 Idiopathic PAH • Symptoms and signs of PAH (exertional dyspnea,
2 PH due to left-sided heart disease
1.2 Heritable PAH syncope, elevated jugular-vein pressure, pedal
Subcategory
edema)
1.3 Drug- and toxin-induced PAH
• Signs of connective tissue disease, HIV infection, 2.1 PH due to heart failure with preserved LVEF
1.4 PAH associated with: or liver disease 2.2 PH due to heart failure with reduced LVEF
1.4.1 Connective-tissue disease
• Echocardiographic signs limited to right heart 2.3 Valvular heart disease
1.4.2 HIV infection chambers
1.4.3 Portal hypertension 2.4 Congenital or acquired cardiovascular conditions
• Other features (history of substance abuse [e.g., leading to postcapillary PH
1.4.4 Congenital heart disease methamphetamines], exposure to drugs or toxins
1.4.5 Schistosomiasis [e.g., fenfluramine, dexfenfluramine, dasatinib], Clinical characteristics
1.5 PAH long-term responders to calcium- family history) • Symptoms and signs of left-sided or valvular heart
channel blockers disease
Hemodynamic profile
1.6 PAH with overt features of venous or • Echocardiographic signs of left-sided or valvular
capillary involvement (PVOD or PCH) • Precapillary PH (mPAP >20 mm Hg, PAWP ≤15 heart disease in addition to right-sided heart signs
1.7 Persistent PH of the newborn mm Hg, PVR ≥3 WU)
Hemodynamic profile
• Isolated postcapillary PH (mPAP >20 mm Hg, PAWP
>15 mm Hg, PVR <3 WU)
mPAP
>20 mm Hg • Combined precapillary and postcapillary PH (mPAP
>20 mm Hg, PAWP >15 mm Hg, PVR ≥3 WU)
based on similar clinical and pathological find- ly in developing countries,13 it is estimated that
ings and treatment responses (for a discussion there are 25 cases of congenital heart disease–
of the historical background, see the Supple- associated pulmonary arterial hypertension per
mentary Appendix, available with the full text of 1 million population worldwide.14 Valvular and
this article at NEJM.org). Idiopathic pulmonary left-sided heart disease are much more com-
arterial hypertension has replaced the term pri- mon,15,16 and more than 100 million persons
mary pulmonary hypertension, in recognition of may have pulmonary hypertension due to left-
the hemodynamic and clinical similarities to sided heart disease (group 2) worldwide.
other conditions that directly affect the pulmo- Similarly, pulmonary hypertension compli-
nary arterial vasculature and for which targeted cates chronic lung diseases, such as chronic
therapy is available. obstructive pulmonary disease (worldwide bur-
The recognition that some persons have a den, >500 million cases) and interstitial lung
genetic predisposition to the disorder (familial disease (estimated incidence, 10 to 70%); the
pulmonary arterial hypertension) led to the land- prevalence is increased among patients with ad-
mark discovery of mutations in the gene encod- vanced disease.14 In addition, more than 140 mil-
ing bone morphogenetic protein (BMP) receptor lion persons live at high altitude (above 2500 m),17
type 2 (BMPR2).8,9 Since 80% of cases of familial but the prevalence of pulmonary hypertension
pulmonary arterial hypertension and up to 20% due to chronic hypoxia among persons living in
of sporadic cases have germline BMPR2 muta- high-altitude areas or persons relocating to such
tions, and since additional mutations in various areas is unclear. Furthermore, pulmonary hyper-
genes have been identified, the term familial tension complicates highly prevalent viral infec-
pulmonary arterial hypertension was subsequent- tions (e.g., human immunodeficiency virus [HIV]
ly changed to heritable pulmonary arterial hyper- infection) and parasitic diseases (e.g., schistoso-
tension. miasis), as well as hemoglobinopathies such as
In the first two decades of this century, a sickle cell disease and thalassemia; therefore,
flurry of novel oral, injectable, and inhaled drugsvery large numbers of patients are affected in
emerged, prompted by a growing interest in and low- and middle-income areas of Africa, Asia,
understanding of pulmonary arterial hyperten- and South and Central America.18,19
sion. The development of these drugs followed Thus, it is estimated that 1% of the world
and was based on various well-conducted, placebo- population and up to 10% of persons older than
controlled studies (Fig. S1 in the Supplementary 65 years of age have pulmonary hypertension.14
Appendix). Moreover, 80% of these persons live in develop-
ing countries and, because of prohibitive cost,20
lack of approved drugs, or limited access to
A Gl ob a l He a lth Probl em
necessary medical and surgical support (e.g., for
The prevalence of pulmonary hypertension var- the treatment of chronic thromboembolic pul-
ies according to the WSPH group classification. monary hypertension [group 4]), are unlikely to
Pulmonary arterial hypertension (group 1) af- receive therapy.12,14
fects 25 persons (most of whom are women) per
1 million population in Western countries, with Pathol o gic a l Fe at ur e s
an annual incidence of 2 to 5 cases per million.10
The disease is most severe in elderly men, al- The histologic features of pulmonary arterial
11
though it is less common in this population, hypertension are complex and variable because
which is more likely to have group 2 disease. For of the multiplicity of underlying diseases. How-
other groups in the pulmonary hypertension ever, there are common pathological features of
classification, the prevalence varies according to the disorder, such as remodeling of the three
the cause and disease state but is likely to be layers of the distal pulmonary vasculature
greatly underestimated worldwide.12 (Fig. 2), which involves uncontrolled growth of
Many widespread diseases of the cardiopul- endothelial and smooth-muscle cells and fibro-
monary systems are complicated by pulmonary blasts,22 and infiltration of inflammatory cells,23
hypertension, which greatly increases morbidity which affects primarily precapillary vessels with
and mortality. Owing to the high prevalence of a caliber of 50 to 500 μm. There is also exten-
congenital heart diseases worldwide, particular- sion of the smooth-muscle cell layer to typically
Medial hypertrophy
SMC hyperplasia
Inflammatory-cell
recruitment
Fibroblast proliferation
Collagen disruption
Remodeled pulmonary vessel in PAH
BMP9, BMP10
(GDF2, BMP10)
Figure 2 (facing page). Pathobiologic Features of Pulmonary nonmuscularized distal capillaries. Postcapillary
Arterial Hypertension. vessels with similar vein remodeling may be in-
Panel A shows a normal distal pulmonary artery and a PAH ves- volved in specific syndromes, such as pulmonary
sel characterized by remodeling of the three vessel-wall layers veno-occlusive diseases and pulmonary capillary
(intima, media, and adventitia [EEL denotes external elastic lami- hemangiomatosis, scleroderma-associated pulmo-
na, IEL internal elastic lamina, and SMC smooth-muscle cells]).
nary arterial hypertension,24 chronic thrombo-
Endothelial-cell (EC) apoptosis and proliferation cause intimal
thickening, smooth-muscle cell hyperplasia causes medial embolic pulmonary hypertension,25 and group 2
thickening, and infiltration of inflammatory cells such as mono- cardiac diseases in which vascular remodeling
cytes, B and T lymphocytes, and dendritic cells, along with colla- may start in the postcapillary compartment.26 In
gen disruption, contribute to adventitial remodeling. In Panel B, situ thrombosis involving small muscular arteries
an elastic stain of a distal pulmonary vessel shows marked nar-
has long been recognized22 as being due to plate-
rowing of the arterial lumen, with concentric laminar intimal
proliferation and fibrosis, and destruction of the IEL (arrow). let activation and loss of endothelial integrity.27
The elastic stain in Panel C shows total occlusion of a small These changes result in luminal narrowing or
pulmonary artery (arrow). Panel D (hematoxylin and eosin) complete obliteration of small vessels. Plexiform
shows a plexiform lesion with an occlusive lesion proximally lesions, which may arise from anastomoses in-
(arrowhead) and excessive, poorly formed capillaries and large
volving bronchial arteries or vasa vasorum pene-
clusters of endothelial-like cells distally (arrows). Panel E (hema-
toxylin and eosin) shows a characteristic lesion of PVOD, with trating the wall structure of pulmonary vessels,28
intimal fibrosis (arrow) and marked obliteration of the vessel lu- are common features of pulmonary arterial
men. The diagram in Panel F (adapted from Southgate et al.21) hypertension (Fig. 2). Events leading to severe
shows signal transduction by transforming growth factor β remodeling have not been clearly identified,
(TGF-β) superfamily members and related genes and proteins
although endothelial dysfunction induced by
implicated in heritable PAH, including membrane-bound re-
ceptors such as bone morphogenetic protein receptor type II shear stress, hypoxia, autoimmune phenomena,
(BMPR2); activin A receptor type II–like 1 (ACVRL1), also known viral infections, drugs and toxins, or genetic al-
as activin receptor–like kinase 1 (ALK1); endoglin (ENG); caveo- terations may initiate the process of excess vaso-
lin-1 (CAV1); and transcription factors SMAD4 and SMAD8 constriction, inflammation, and uncontrolled
(SMAD4 and SMAD9). Bone morphogenetic protein (BMP)
cellular growth.27 The findings of highly orga-
signaling is mediated, in a cell specific manner, by the binding of
ligands BMP9 and BMP10 to a heterometric complex of BMPR-II, nized lymphoid follicles juxtaposed against pul-
a cognate type 1 receptor (ACVRL1 or ALK1), and endoglin, an monary arterial hypertension lesions, infiltra-
auxiliary receptor thought to sequester ligand, inhibiting recep- tion of T and B lymphocytes,29 and circulating
tor binding and thus modulating the effects of BMPs. Activation inflammatory markers correlating with disease
of the receptor complex results in phosphorylation of the recep-
severity,30 combined with the fact that pulmo-
tor and SMAD8, which then associates with SMAD4 before
translocation to the nucleus, regulating genes that contain nary arterial hypertension often complicates auto-
BMP-responsive elements (BREs). KCNK3, the gene encoding immune or inflammatory diseases, have all lent
potassium-channel subfamily K, member 3 (K2P3.1), contributes substantial credence to a role of inflammation
to pulmonary vascular tone and is a subunit of the ATP-sensitive in the pathogenesis of pulmonary arterial hyper-
potassium (K ATP) channel (ABCC8). SOX17 and TBX4 (transcrip-
tension.23,31
tion factors important for organogenesis) also participate in
BMP signaling. The probable cation-transporting ATPase 13A3
(ATP13A3) is not directly related to BMP signaling. However, R igh t V en t r icl e
loss-of-function mutations in ATP13A3 disrupt polyamine homeo-
stasis and lead to endothelial dysfunction, thus contributing to Right ventricular function is the major determi-
PAH pathogenesis. Aquaporin 1 (AQP1), also not a member of
nant of clinical outcomes and survival among
the TGF-β superfamily, mediates the migration and proliferation
of pulmonary-artery smooth-muscle cells by interacting with patients with pulmonary hypertension.32 In re-
β-catenin to activate cell growth–related target genes. Biallelic sponse to an increase in pulmonary vascular
mutations in GCN2 (general control nonderepressible 2), also resistance by a factor of 5 to 10, the right ven-
known as EIF2AK4 (eukaryotic translation initiation factor 2 alpha tricle undergoes hypertrophy, chamber dilata-
kinase 4), which encodes an important kinase in the integrated
tion, fat deposition, fibrosis, and metabolic shifts
stress response, are associated with the pathogenesis of PVOD
and PCH. as pulmonary hypertension progresses.32
Right ventricular remodeling may be adap-
nary capillary hemangiomatosis52 and pulmo- tially delayed diagnosis in many cases. The pres-
nary veno-occlusive disease53 and in up to 25% ence of an underlying disease such as HIV infec-
of sporadic cases of these diseases. More re- tion or liver or connective-tissue disease or a
cently, germline mutations of TET2, encoding history of exposure to drugs or toxins should
ten-eleven translocation (tet) methylcytosine di- heighten suspicion concerning pulmonary arte-
oxygenase 2, a key enzyme in DNA demethyl- rial hypertension (Fig. 1). A major diagnostic
ation, were reported in a large cohort of patients challenge is to rule out other forms of pulmo-
with pulmonary arterial hypertension.54 nary hypertension for which management should
The role of altered BMPR-II signaling in the focus principally on the underlying disease, so
pathogenesis of pulmonary arterial hypertension risk factors for or symptoms of left-sided heart
cannot be overestimated. Most discovered muta- disease or chronic lung disease are important to
tions involve BMPR2 or genes encoding proteins consider.
that form complexes or interact with BMP or Physical findings that are suggestive of pul-
BMPR-II signaling (Fig. 2). BMPR-II functional monary hypertension include an increased sec-
loss leads to endothelial dysfunction and the ond pulmonic sound, a murmur of tricuspid re-
altered balance between proliferation and apo gurgitation, and evidence of right ventricular
ptosis that is characteristic of pulmonary arterial fluid overload (e.g., increased jugular venous
hypertension, which explains the growing inter- pressure and pedal edema). Other findings might
est in therapy aimed at increasing BMPR-II ex- suggest an underlying cause of pulmonary hy-
pression55 or ligand levels, as attempted in pre- pertension, including sequelae of chronic liver or
clinical models of BMP9 administration.56 rheumatologic disorders.
Clinicians have an ethical obligation to inform
patients and their families about any existing Diagnostic Testing
genetic condition, particularly in the case of idio- Transthoracic echocardiography (TTE), the sin-
pathic or heritable pulmonary arterial hyperten- gle most important screening test (Fig. 3), pro-
sion, pulmonary veno-occlusive disease, or pulmo- vides a set of measures for gauging the preva-
nary capillary hemangiomatosis, and congenital lence, cause, and severity of the disease. These
heart disease–associated pulmonary arterial hy- measures include dilatation of right-sided cham-
pertension. The implications for family members bers; presence and severity of tricuspid regurgi-
and their offspring who may be mutation carri- tation, which allows for an estimation of right
ers should be considered, along with screening, ventricular systolic pressure; the presence of
genetic and psychological counseling by a mul- pericardial effusion; and abnormal septal devia-
tidisciplinary team of experts, and patient edu- tion due to right ventricular volume and pressure
cation.57 Several affordable technologies and overload. TTE can also identify left ventricular
platforms can be used to probe multiple genes systolic or diastolic dysfunction and valvular ab-
simultaneously. normalities, findings that shift the focus toward
Genetic testing, which promises to further group 2 pulmonary hypertension.
our understanding of the disease and improve In addition to a complete blood count and
therapy through specific targeting, is a task of metabolic panel, measurement of antinuclear
several national and international collaborative antibody titers and HIV serologic testing may
studies58 and the National Institutes of Health– help uncover a specific underlying disorder such
sponsored PVDOMICS (Pulmonary Vascular Dis- as connective-tissue disease or HIV disease, re-
ease Phenomics) initiative.59 spectively. The serum N-terminal natriuretic
peptide level, measured as a nonspecific cardiac
biomarker, can be incorporated into risk strati-
Di agnosis
fication (see the discussion below), since the
History and Physical Examination value tracks with the severity of pulmonary arte-
Symptoms of pulmonary arterial hypertension rial hypertension and can be used to predict
are nonspecific (exertional dyspnea, fatigue, chest survival.61
pain, and fluid retention, as well as syncope in A chest radiograph may suggest cardiac en-
advanced cases), which accounts for a substan- largement and dilated pulmonary arteries, as
hypertension in asymptomatic patients with the ESC-ERS “risk table” and other risk scores (e.g.,
scleroderma spectrum of diseases.62 An electro- the REVEAL [Registry to Evaluate Early and
cardiogram is important to look for evidence of Long-Term PAH Disease Management] risk score
atrial or ventricular hypertrophy, signs of ische calculator66) (Fig. S4) have been successfully
mic heart disease, or dysrhythmias. used to assess survival in retrospective analyses
Cardiac MRI (Fig. S3) is the standard for right of data from pulmonary arterial hypertension
ventricular assessment because it provides accu- registries67-69 and a post hoc analysis of data
rate measurements of the cardiac chamber anat- from a large prospective clinical trial.70 The pre-
omy and volume, mass, function, and flow, as dictive ability of stratification methods is im-
well as myocardial perfusion.38 Not widely avail- proved by machine-learning algorithms, which
able, it is increasingly used in centers with ex- reveal a dynamic interdependent influence of
pertise in diagnosing and managing pulmonary multiple risk factors, thus avoiding the assump-
hypertension. Other advanced imaging tech- tion that limited clinical measures have indepen-
niques that remain in the realm of research in- dent relationships to a specific outcome.71
clude three-dimensional echocardiography, four-
dimensional flow MRI, and positron-emission Ther a py
tomography, which can provide unique insights
into right ventricular metabolic activity.63 Basic supportive measures, a constant compo-
nent of treatment long before the availability of
Hemodynamics targeted therapy, include diuretics to achieve
Right heart catheterization is required for the euvolemia and supplemental oxygen when need-
diagnosis of pulmonary arterial hypertension in ed at rest, during sleep, or with exercise, to main-
order to directly assess pulmonary hemodynam- tain adequate hemoglobin oxygen saturation
ics and cardiac output and to calculate pulmo- (Fig. 4). Sleep-disordered breathing, which can
nary vascular resistance. This is a necessary step complicate any form of cardiopulmonary disor-
in the diagnostic algorithm before treatment der, is prevalent among patients with precapil-
(Fig. 3). It is essential for confirmation of the lary pulmonary hypertension72 and should be
presence and type of pulmonary hypertension diagnosed and treated when appropriate. Anti-
(precapillary, postcapillary, or combined) and coagulant therapy, once recommended on the
provides essential measures for risk stratification. basis of retrospective analyses showing a sur-
A structured clinical assessment (Fig. 3) helps vival benefit,73,74 is now recommended only for
assign a patient to a specific pulmonary hyper- idiopathic pulmonary arterial hypertension (not
tension group (Fig. 1), which is essential in de- for other forms of pulmonary arterial hyperten-
termining the appropriate therapy, although it is sion, according to data from a European regis-
increasingly clear that any given patient may try),75 on a case-by-case basis and risk–benefit
belong in more than one group. analysis, and for group 4 pulmonary hyperten-
sion (CTEPH), in which increased clotting is a
primary issue. A cardiopulmonary exercise pro-
R isk S t r at ific at ion
gram is advised on the basis of a meta-analysis
The importance of risk assessment was recog- of controlled trials,76 as tolerated by the patient
nized early in the study of idiopathic pulmonary (Fig. 4). Immunizations should be kept up to date.
arterial hypertension, at which time the focus Although four decades separated the initial
was essentially on baseline hemodynamics.64 The clinical description of pulmonary hypertension
2015 European Society of Cardiology–European and approval of the first effective therapy for
Respiratory Society (ESC-ERS) guidelines for pulmonary arterial hypertension, based on a ran-
pulmonary hypertension65 highlighted as an in- domized, non-placebo-controlled trial of prosta-
creasing priority the stratification of patients, at cyclin in patients with “primary pulmonary hy-
baseline and follow-up, into low-, intermediate-, pertension,”77 the past 20 years have witnessed a
and high-risk groups on the basis of a combina- series of clinical trials targeting essentially three
tion of clinical, functional, and hemodynamic signaling pathways identified in pulmonary ar-
measures, as a tool for choosing therapy. The terial hypertension78 (Fig. 5). These trials have
Confirmed PAH
General supportive measures No acute vasodilator response Positive acute vasodilator response
Diuresis to achieve euvolemia before (>90% of patients) (<10% of patients)
therapy and after initiation of targeted Drop in mPAP >10 mm Hg to absolute
therapy value ≤40 mm Hg
Supplemental O2 to treat hypoxemia No change or increase in CO
at rest, during sleep, or with exercise
Anticoagulation for idiopathic PAH
or as indicated
Diet and exercise
High-dose calcium-channel blocker
Contraceptive measures for women
of childbearing age Risk assessment Ensure adequate response (FC I or II
Referral for counseling and genetic ESC-ERS risk stratification and improved hemodynamics)
testing as appropriate REVEAL score Add PAH-targeted therapy for lack of
Vaccinations as appropriate adequate response or loss of acute
vasodilator response on repeat
testing at 1 yr
Oral monotherapy if response Oral dual therapy, either Combination therapy including Evaluation for lung
is adequate or if dual therapy up-front or sequential parenteral PGI2 agent transplantation
is poorly tolerated (for patients with incomplete
response to monotherapy)
Intermediate or
Low risk
high risk
established current targeted therapy for pulmo- ception of inhaled treprostinil, which is now
nary arterial hypertension (group 1) and CTEPH approved by the Food and Drug Administration
(group 4). The findings do not apply to other (FDA) for pulmonary hypertension associated
groups in the WSPH classification, with the ex- with interstitial lung disease (group 3) on the
BLOOD-VESSEL
L-citrulline
LUMEN PGI2
ENDOTHELIAL
CELL eNOS
Proendothelin Arachadonic L-arginine
acid Nitric oxide
Cox 1/2
+
Gs Sildenafil
sGC PDE5 – Tadalafil
Adenylate
Vasoconstriction Vasodilatation cyclase GTP cGMP GMP
Proliferation Proliferation
ATP cAMP
SMOOTH-MUSCLE CELLS
–
– – Vasodilatation
Bosentan Vasodilatation Proliferation
Macitentan Proliferation
Ambrisentan
basis of a recent randomized phase 3 clinical therapy with pulmonary endarterectomy should
trial.79 An assessment for CTEPH is best per- be considered first. Medical therapy, pulmonary
formed at specialized centers, where definitive balloon angioplasty, or both are considered for
patients with inoperable disease or residual pul- therapy on survival in most of the more recent
monary hypertension after endarterectomy. large RCTs,81,82,84 a large meta-analysis of early
There have been important changes in the RCTs evaluating therapy for pulmonary arterial
design of randomized, controlled trials (RCTs) hypertension, averaging 12 to 16 weeks in dura-
over approximately the past decade. The 6-min- tion, showed a significant reduction in mortality
ute walk distance was the primary end point in with therapy as compared with placebo,85 which
most early RCTs, typically with a 12-week study is consistent with data obtained from large reg-
period. However, in response to various calls for istries.86,87
establishing more relevant end points,80 RCTs Treatment algorithms designed to guide ther-
shifted to composite end points, including a apy, with classes of recommendations and the
combination of hospital admission, worsening level of evidence for the various therapies ap-
of pulmonary arterial hypertension, mortality, proved for pulmonary arterial hypertension, are
and escalation of therapy. Another important available in comprehensive guidelines.65 Patients
change in RCT design was an evaluation of the who have pulmonary vasoreactivity (typically to
new therapy added to background treatment inhaled nitric oxide during initial right heart
for pulmonary arterial hypertension or up-front catheterization), based on strict criteria (a re-
combined therapy rather than monotherapy. duction in mean pulmonary arterial pressure of
These changes required the enrollment of many ≥10 mm Hg, to an absolute value of ≤40 mm Hg,
more patients and a longer time to reach the accompanied by an increase or no change in
primary outcomes. An example is SERAPHIN cardiac output), can be treated with high-dose
(Study with an Endothelin Receptor Antagonist calcium-channel blockers alone, provided that
in Pulmonary Arterial Hypertension to Improve this therapy results in New York Heart Associa-
Clinical Outcome), which revealed the efficacy of tion (NYHA) functional class I or II with hemo-
macitentan, a dual endothelin receptor antago- dynamic improvement maintained on repeat
nist, in reducing the first occurrence of a com- testing after at least 1 year of therapy1 (achieved
posite primary end point in a study population in less than 10% of patients with idiopathic
of more than 700 patients with symptomatic pulmonary arterial hypertension88). In case of
pulmonary arterial hypertension who were re- clinical deterioration or loss of vasoreactivity,
ceiving placebo or background therapy (inhaled pulmonary arterial hypertension–specific ther-
or oral drugs, excluding other endothelin re- apy should be added according to accepted algo-
ceptor antagonists).81 A subsequent RCT, the rithms.
AMBITION (Ambrisentan and Tadalafil in Pa- Monotherapy can be used for patients with a
tients with Pulmonary Arterial Hypertension) positive response to acute vasoreactivity and
trial, compared up-front combination therapy those with a good historical response (NYHA
with two FDA-approved drugs (ambrisentan and functional class I or II with sustained hemody-
tadalafil) with each drug alone in patients who namic improvement), elderly patients (>75 years
had received no previous treatment for pulmo- old) with important risk factors for left-sided
nary arterial hypertension.82 The risk of the pri- heart disease (e.g., systemic hypertension, coro-
mary end point (the first event of clinical failure nary artery disease, or atrial fibrillation), those
in a time-to-event analysis) was reduced with suspected of having pulmonary veno-occlusive
combination therapy as compared with mono- disease or pulmonary capillary hemangiomato-
therapy with either drug. In both of these large sis, patients with very mild disease (NYHA func-
trials, however, the primary end point was driv- tional class I and pulmonary vascular resistance
en predominantly by decreased hospitalization of 3 to 4 WU, with normal right ventricular
rates (essentially due to worsening pulmonary function on echocardiography), and patients in
arterial hypertension), a clinically relevant out- whom combination therapy is associated with
come, since admission for right ventricular fail- an unacceptable side-effect profile.60 Otherwise,
ure, the main cause of hospitalization among most patients with pulmonary arterial hyperten-
patients with pulmonary arterial hypertension, sion are currently treated with up-front combi-
portends a very poor prognosis.83 nation therapy consisting of two oral agents,
Despite the lack of an effect of combined oral with dose escalation within a drug class when
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