Download Pulmonary arterial hypertension, a rare entity

REVIEW ARTICLE
Pulmonary arterial hypertension, a rare entity
Jaime Eduardo Morales-Blanhir,* Andrés Eduardo Carmona-Rubio,† María de Jesús Rosas-Romero,*
Gloria Silene Vergara de Márquez,‡ Guillermo Adolfo Arbo Oze de Morvil§
*Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. FEMEXER.
†Universidad de Buffalo, Universidad Estatal de Nueva York.
‡ Sociedad Venezolana de Cardiología. Unidad de Hipertensión Pulmonar del Hospital Clínico. Maracaibo. Venezuela.
§Sociedad Paraguaya de Neumología. Asunción, Paraguay.
ABSTRACT
Hipertensión arterial pulmonar, una entidad rara
RESUMEN
Pulmonary arterial hypertension (PAH) is a rare disease. It is
characterized by the progressive remodeling of the small pulmonary arteries that lead to an elevation of the pulmonary
vascular resistance and right ventricular dysfunction. Early
diagnosis and prompt treatment avoid the deterioration of the
patient’s quality of life. Statistics show that there are 15 cases
per million people worldwide, the majority composed of young
women, with an age at diagnosis of 30 to 40 years. At present,
the exact processes that initiate the pathophysiologic changes
observed in PAH are unknown; it is thought to be multifactorial. Diagnosis in PAH must be done in a step by step manner.
Under the suspicion of pulmonary hypertension (PH), the
first thing to do is confirm the diagnosis. The second step is to
identify the specific etiology and lastly evaluate the severity by
echocardiography, hemodynamic parameters, biomarkers and
exercise capacity. PH treatment, particularly PAH, has evolved over the last 2 decades due to the advance in disease
knowledge and the availability of agents that act on different
pathways. Concerning surgical treatment, it is indicated in
PAH when there is not an adequate response to medical treatment. In conclusion, PAH is recognized worldwide as a rare or
infrequent disease. The countries that have a registry for the
diagnostics, treatment, follow-up and prevalence of PH are
mainly in Europe. With the exception of the United States and
Canada, there are no registries in America. Recent years have
shown an important advance in Latin America.
La hipertensión arterial pulmonar (HAP) es una enfermedad
rara que se caracteriza por un aumento progresivo de la resistencia vascular pulmonar, que conlleva a la insuficiencia
cardiaca derecha y la muerte prematura. Su diagnóstico y
tratamiento temprano es esencial para tener un impacto en el
pronóstico a largo plazo. Las estadísticas reportan 25 casos/
millón de habitantes, principalmente en mujeres, con una
edad de diagnóstico entre 30/40 años. Se conoce que algunos
de los procesos que desencadenan los cambios fisiopatológicos son multifactoriales. Ante la sospecha, primero confirmar el diagnóstico, identificar la clase de hipertensión
pulmonar (HP) de acuerdo con la clasificación y, por último,
realizar estudios adicionales para identificar el tipo de HAP.
El tratamiento de la HP, en especial de la HAP, ha permitido
la aprobación de varias terapias específicas que confieren
mejoras en la clínica, hemodinámica, calidad de vida y sobrevida. El tratamiento quirúrgico está indicado posterior a
no obtener una respuesta adecuada en el tratamiento médico. En conclusión, la HAP se conoce como una enfermedad
rara o huérfana, los países que llevan un registro en el diagnóstico, tratamiento, seguimiento y prevalencia son en su
mayoría europeos; en América, exceptuando Estados Unidos
y Canadá, no se cuenta con registros; sin embargo, en los últimos años existen avances importantes en Latinoamérica.
Key words. Pulmonary hypertension. Pulmonary arterial
hypertension. Echocardiography.
Palabras clave. Hipertensión pulmonar. Hipertensión arterial pulmonar. Ecocardiografía.
INTRODUCTION
vation in the pulmonary vascular resistance (PVR),
which leads to right ventricular failure and premature death.1 National Institute of Health (NIH)
PAH patient registry in the United States reported a
Pulmonary arterial hypertension (PAH) is a rare
disease that has been described as a progressive ele-
Rev Invest Clin2014
Morales-Blanhir
JE, et al. Clínica
Pulmonary
arterial
hypertension.
2014;/ 66
65-78
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de Investigación
/ Vol.
66, Num.
1 / January-February,
pp (1):
65-78
Full text of this article available in internet: www.imbiomed.com.mx
65
mean age of 35.9 ± 12.2 years, female-male ratio of
2.4:1.2 The prevalence is 25 cases per million people
in Switzerland/France,3,4 and in Scotland 26 cases
per million people.5 Information available concerning PAH in Latin America is limited.
PAH is defined as the rise in the mean pulmonary
arterial pressure (mPAP) > 25 mmHg at rest, determined by right heart catheterization (RHC).6,7 The definition of PAH during exercise (mPAP > 30 mmHg) is
no longer used due to lack of scientific evidence.7-8
Valerio, et al., observed patients with scleroderma and
mPAP 21-24 mmHg, where initially they found an elevated transpulmonary gradient that ended in developing pulmonary hypertension during follow up.9
Physiopathology concerning pulmonary arterial
hypertension (PAH) is currently unknown and it is
thought to be multifactorial. The most important
function of the pulmonary endothelium is PVR
maintenance. The rise of PVR is related to different
mechanisms which include vasoconstriction, pulmonary vascular wall remodeling (proliferative and obstructive), inflammation and thrombosis. Excessive
vasoconstriction has been related to anomalous expression of potassium channels in smooth muscle
cells and endothelial dysfunction. The latter generates a chronic deficiency of vasodilators and proliferative agents [nitric oxide (NO) and prostacyclins],
along with the overexpression of vasoconstrictive
and vasodilator substances (thromboxane A2 and endothelin-1).6,7
Several genetic alterations have been identified
through biomolecular techniques and developing experimental models. The term hereditary PAH
(HPAH) includes familial PAH (PAH present in one
or two members of the family) and simple PAH (only
one subject in a family) when a spontaneous mutation is identified. In 75% of reported HPAH cases a
1
2
3
66
Set treatment
goals
,
Establish patient s
mutation in the gene that codes the bone morphogenetic protein type 2 (BMPR2) was detected. Other
mutations were also found (ACVRL1, BMPR1B,
CAV1, ENG, SMAD9) but are less common (< 1%).
HPAP presents itself with the same signs, symptoms
and histologic changes as idiopathic PAH. The time
from the initiation of symptoms to diagnosis can be
shorter in individuals with familial PAH due to the
presence of higher suspicion. Three retrospective
clinical trials suggest that patients with a mutation
in the BMPR2 present it self with severe disease. 10
Prenatal testing in high risk pregnancies is an excellent alternative in a family with a confirmed diagnosis of familial PAH.11
Any condition considered to predispose or facilitate PAH is considered a risk factor. Initial clinical
values are important for risk assessment. However,
their utility for prognosis is limited because they can
change with time and intervention. The evaluation
of the goals of therapy in PAH, using the criteria
established in the guidelines of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) are reflected in figure 1. Future
investigations must be focused in developing a dynamic scoring system to evaluate time dependent
variables over clinical results.12
Different classifications of pulmonary hypertension (PH) allow investigators to organize the data
collected from patient registries and clinical trials.
During the 2008 International Symposium in Dana
Point it was decided to maintain the current structure with a five group classification.13,14 The same
classification was kept in Nice 2013, were the main
discussions involved topics in: genetics, congenital
or acquired left heart diseases (e.g. outflow and inflow tract obstructions), developmental lung diseases and other uncertain multifactorial entities.
Rate of progression
WHO-FC
Syncope
6MWD
Echo findings
CPET
BNP/NT proBNP
Haemodynamics
Clinical evidence of right heart failure
clinical status
Stable and
satisfactory
Review treatment
regimen
No change
Stable and not
satisfactory
Unstable and
deteriorating
Escalation
Figure 1. Risk assessment and treat-to-target approach for pulmonary arterial hypertension.
WHO-FC: World Health Organization-functional
class. 6MWD: 6-min walking distance. CPET:
cardiopulmonary exercise testing. Echo: echocardiography. BNP: brain natriuretic peptide. NTproBNP: N-terminal-pro-brain natriuretic peptide.
Adapted from Rubin, et al. 201212, with permission from the publisher.
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
Analysis of the data involving survival from the
latest cohorts of PAH is biased by patients included
months or years after their diagnosis (survivors)
who have a better prognosis than patients newly diagnosed during the evaluation. Critical analyses of
the cohorts show an improved survival. However,
idiopathic PAH is still a severe disease with poor
prognosis.15
DIAGNOSTICS
Upon suspecting PH the first thing is confirming
the diagnosis. The second is identifying the class of
PH. Lastly, performing tests to find out the type of
PAH, figure 2. Idiopathic PAH is considered a diagnosis of exclusion.
Symptoms/Signs/History suggestive of PH
Noninvassive assessment compatible with PH?
Search for other
causes and/or re-check
No
Yes
Consider common causes of PH
Group 2:
left heart disease?
Group 3: lung diseases
and/or hypoxia?
History, symptoms, signs
ECG, chest radiograph
TTE, PFT, HRCT
Group 2 or 3: diagnosis confirmed
Yes
PH “proportionate” to severity
NO
Yes
“out of proportion” PH
Treat underlying disease
and check for progression
Perform V’/Q’ scan
Segmental perfusion defects
Consider group 4:
CTEPH
Yes
NO
Search for
other causes
Consider other uncommon causes
NO
Perform RHC
(PAH probability*)
Ppa ≥ 25 mmHg
Ppcw ≤ 15 mmHg
Consider
PVOD/PCH
Specific diagnostic tests
PVOD
PCH
Clinical signs HRCT, ANA
CTD
History
Drugs,
toxins
HIV test
TTE,
TEE,
CMR
Yes
Physical,
US,
LFT
Physical,
laboratory analysis
Portopulmonary
HIV
CHD
Idiopathic or heritable PAH
Schistosomiasis,
other group 5
Chronic haemolysis
BMPR2, ALK-1, endoglin
(HHT), family history
Figure 2. Diagnostic algorithm. ALK-1: activin-receptor-like kinase. ANA: anti-nuclear antibodies. BMPR2: bone morphogenetic protein receptor 2.
CHD: congenital heart disease. CMR: cardiac magnetic resonance. CTD: connective tissue disease. CTEPH: chronic thromboembolic pulmonary hypertension. Group: clinical group. HHT: hereditary haemorrhagic telangiectasia. HRCT: high-resolution computed tomography. LFT: liver function tests. Ppa:
mean pulmonary arterial pressure. PAH: pulmonary arterial hypertension. PCH: pulmonary capillary haemangiomatosis. Ppcw: pulmonary capillary wedge
pressure. PFT: pulmonary function test. PH: pulmonary hypertension. PVOD: pulmonary veno-occlusive disease. RHC: right heart catheterization. TEE:
transoesophageal echocardiography. TTE: transthoracic echocardiography. US:ultrasonography. V’/Q’: ventilation/perfusion lung scan. Adapted from
Galiè, et al. 20097 with permission from the publisher.
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
67
An important consideration in Latin America is
the fact that some countries do not have PH qualified physicians and in some places, especially rural
areas, it is hard to find hospitals with the necessary
equipment to perform diagnostic tests.16
Clinical suspicion of PH is based on the symptoms,
signs and the presence of risk factors.7,17-18 Detection
requires studies to confirm the diagnosis: electrocardiogram, chest radiography and Doppler echocardiogram. The latter is a very useful tool in the
diagnosis19-23 and screening of patients with risks of
developing PAH, e.g. congenital cardiomyopathies,
venous thrombosis, connective tissue disorders, human immunodeficiency virus (HIV) or the exposure
to toxics associated with PAH.6-7 The identification of
the type of PH requires several diagnostic tests. Pulmonary function tests (PFTs) and high resolution
computerized tomography (HRCT) of the chest, to
rule out left sided cardiomyopathies (group 2) or lung
diseases (group 3).24-26 If there is no evidence of
the mentioned pathologies or PH disproportionate to the
underlying condition, pulmonary ventilation/perfusion scan (V/Q) which is more sensitive than chest
HRCT for chronic thromboembolic pulmonary hypertension (CTEPH) is the next step [sensitivity (S): 90100%, specificity (E): 94-100%].27,28 If the V/Q shows
multiple perfusion defects CTEPH has to be suspected, for definitive diagnosis RHC has to be performed
and in some cases selective pulmonary angiography.29 Lastly, blood work is done, e.g. HIV, thyroid
testing30 and immunologic workup.31 Other tests
that can be performed are, abdominal ultrasound,32-34
evaluation of exercise capacity (6 min walk and cardiopulmonary exercise test), RHC with pulmonary
vascular reactivity test (PVRT)7 to identify PAH.35-38
Recently, cardiovascular magnetic resonance has
been used to measure and calculate hemodynamic parameters and evaluate the right ventricle (RV).39-41
In relation to the early detection of PAH there
have been important advances. Although, there is
still room for improvement in diagnostics, catheterization and patient management. Definitive diagnosis can be delayed for up to 2 years from the start
of symptoms, which is still a challenge. Targeting
high risk patients can allow early diagnosis in
PAH. However, methods utilized routinely in clinical practice have limitations. A combination of
tools and parameters is required to improve the
sensitivity and specificity. PAH is a disease that
progresses fast, even in patients with mild symptoms and appropriate therapy. This is why early
detection can have a big impact in long term prognosis in PAH patients.42
68
PROGNOSTIC FACTORS
Demographic factors, such as sex or time of initiation of symptoms, are not clearly related to mortality. On the other hand, age (< 14 years or > 65
years of age) and race (Afro-American and Asian)
have been showed to have a worse prognosis.43 Survival between male and females is similar in studies
which were done before and after initiating appropriate therapy.44
Associated PAH pathologies can influence the
prognosis, e.g. multiple sclerosis alone or accompanied by interstitial lung disease, HIV45 and portal
hypertension 32-34 have been shown to have a poor
prognosis. Pregnancy has also been described as
having a poor prognosis in patients with PAH.
Functional class
Clinical assessment provides valuable prognostic
information that can guide patient management.
Syncope, hemoptysis and signs of right ventricular
failure lead to a bad prognosis, as well as, rapid progression of the latter. Although there is great variation between observers measuring World Health
Organization Functional Class (WHO-FC), it still
remains an important indicator of survival. Patients
with WHO-FC I and II have a better prognosis than
WHO-FC III or IV. In the NIH Registry, mean survival of patients with mild to moderate symptoms
(WHO-FC I and II) was 58.6 months compared to
31.5 months in patients who had moderate to severe
symptoms (WHO–CF III) and was 6 months in patients with severe symptoms (WHO-FC IV).46
Exercise capacity
An important parameter utilized in PAH is the
measurement of exercise capacity. For objective assessment we use the 6 min walk (6MW)47 and the
cardiopulmonary exercise test (CPET). 6MW is simple, economic, reproducible and standardized. On
top of the distance walked, the amount of dyspnea
during exercise is measured using the Borg Scale
and oxygen saturation is measured through digital
pulse oximetry. The 6MW is done at the time of diagnosis and it helps assess response to treatment.
Walking a distance of < 332 meters or < 250 meters
and having an oxygen desaturation > 10% are indicators of bad prognosis in PAH.7 In a recent study,
the evaluation of the pulmonary function during
CPET demonstrated that patients with PAH have a
ventilator equivalent for CO 2 (VECO2) < 48, peak
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
oxygen consumption (peak VO2) > 13.2 mL/kg/min,
delta O2 > 3.3 mL/min, 6MW of 399 m and an increased accumulative survival compared to patients
that lack the above (p < 0.05).48 Hypocapnia during
rest and exercise is correlated with a low cardiac
output, low VECO2 and as an independent maker of
mortality.49
Biological markers
Biological markers constitute a noninvasive tool
for observation and evaluation of RV dysfunction in
PAH patients. Serum quantification of brain natriuretic peptide (BNP) is of use in PAH patient prognosis,50 levels of BNP is associated with pulmonary
arterial pressure (PAP) and PVR.51 PAP and PVR
values correlate with the rise of BNP and have an
inverse relationship with the cardiac index. Other
biological markers that suggest bad prognosis: hyperbilirubinemia, hyponatremia, hyperuricemia, Von
Willebrand factor elevation and high sensitivity cardiac troponin-t elevation. Takeda, et al., in a study
with 37 PAH patients demonstrated that the rise in
bilirubin levels is a risk factor for mortality.52
Hypeuricemia is common in patients with PAH. Recently, a study proposed investigating the possible
clinical benefit of lowering high levels of uric acid.53
The elevation of high sensitivity troponin-t is associated with advanced WHO-FC and high mortality;
additionally it is related to RV dysfunction and deterioration in the 6MW.54
Hemodynamic and
echocardiographic parameters
Multiple prognostic parameters are generated
through echocardiography: RV area, left ventricle
(LV) eccentricity index or Ryan index, Tei index, tricuspid annular plane systolic excursion (TAPSE)
and the presence of pericardial effusions.7 Patients
without pericardial effusions have been proven to
have a better prognosis.
Hemodynamic parameters measured at rest by
RHC have prognostic values. In the NIH registry,
three hemodynamic variables are associated with
the rise in the risk of mortality: increase in mPAP
[relative risk (RR): 1:16; 95% confidence interval
(CI): 1.05 -1.28]; increase right atrial pressure
(RAP) [RR:1.99; 95% CI: 1.47-2.69] and decrease
cardiac index [RR: 0.62; 95% CI: 0.46-0.82].6 Patients with RAP < 8 mmHg or cardiac index ≥ 2.5 L/
min/m2 have better prognosis than those with RAP
> 8 mmHg or cardiac index ≤ 2.5 L/min/m2.55
TREATMENT
During the last two decades advanced comprehension of the pathogenesis of PAH led to the approval
of different specific therapies bestowing improvement in clinical symptoms, hemodynamics, quality
of life and survival of patients.
The therapeutic algorithm is targeted at PAH
(group 1) patients, it is not appropriate for group 2
and 3. At the moment there is no evidence supporting treatment for uncertain multifactorial mechanisms. Main focus after diagnosis of PAH is to adopt
general measures, initiate supportive medical treatment and send a patient to PH referral centres.7,56
Class of recommendations (CR): I and level of evidence (LE): C.
In Latin America there are referral centers in
most countries, mainly in the more populated cities.16
General measures include daily living activity
recommendations:
•
•
•
•
Physical rehabilitation CR: I-LE: A.
Birth control CR:I-LE: C.
Psychosocial support CR:I-LE: C.
Influenza and pneumococcal immunizations CR:ILE:C.
Supportive medical treatment consists of:
• Oral anticoagulation CR:IIa-LE:C for Idiopathic
PAH and CR:IIb-LE: C for Associated PAH.
• Diuretics CR:I-LE:C.
• Oxygen CR:I-LE:C.
• Digoxin and other inotropic drugs CR:IIb-LE:C.
These treatments are commonly used; although
there are no randomized, controlled clinical trials in
PAH who support their use. 56
Specific medical treatment is established in referral centers using pharmacotherapy that acts
through endothelin, nitric oxide and prostacyclin
pathways that participate in PAH development.
In concordance with the results obtained by RHC,
if the PVRT has a positive response, defined as a decrease in mPAP or < 40 mmHg, maintaining the
same or increased cardiac output, therapy is initiated
with calcium channel blockers (CCB), CR:I-LE:C. If
there is no positive response, other treatment options
need to be explored. According to the WHO-FC:
• WHO-FC II. Ambrisentan, bosentan, macitentan,
riociguat, sildenafil, tadalafil, CR:I-LE:A o B.
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
69
• WHO-FC III. Ambrisentan, bosentan, intravenous epoprostenol (IV), inhaled iloprost,
macitentan, riociguat, sildenafil, tadalafil, subcutaneous (SC) or inhaled treprostinil, CR:I-LE:
A o B. IV Iloprost, IV treprostrinil CR:IIa-LE:C.
Beraprost, CR:IIb-LE:B. Initial combination therapy CR:IIb-LE:C.
• WHO-FC IV: IV epoprostenol CR:I-LE:A o B. Ambrisentan, bosentan, inhaled o intravenous iloprost. Macitentan, riociguat, sildenafil, tadalafil,
inhaled, subcutaneous or intravenous treprostinil CR:IIa-LE:C. Initial combination therapy
CR:IIb-LE:C.
Because there is no well-defined comparison between medications, first line evidence based treatment can not be proposed. Choice of medication is
dependent on multiple factors which include: approval status, form of administration, side effect profile and treatment physician experience/preference.56
In Latin America, knowledge is limited to the medications used as monotherapy and combination therapy illustrated in table 1 and table 2.
Calcium channel blockers
Only 10-15% of PAH patients have a positive
PVRT by RHC, making those candidates eligible to
receive long term CCB, especially nifedipine or
diltiazem. The use of verapamil is not recommended
due to its negative inotropic effect. In a prospective
study with high dose CCB; nifedipine 90-240 mg/day
or diltiazem 360-900 mg/day, significantly improved
prognosis of patients with positive PERT.57 Another
essay showed the utility of 20-40 mg daily doses of
amlodipine. It is important to do hemodynamic and
clinical evaluations on patients 3-6 months after initiating therapy.58
Prostanoids
The utility of prostacyclin’s in patients with PAH
has increased with the synthesis of stable analogs
that possess different pharmacokinetic properties
with similar effects.6,7
Epoprostenol has a short half-life ~3 min; it is
administered via continuous intravenous infusion
Table 1. Drugs for pulmonary hypertension in Latin America.
Pharmacological
Argentina
Brazil
Chile
Colombia
Costa
Rica
Cuba
México
Paraguay
Perú
Venezuela
• Calcium channel blockers
Nifedipine
Diltiazem
Amlodipine
Verapamil
• Prostanoids
Epoprostenol
Treprostinil
Iloprost
Beraprost
• Endothelin receptor antagonists
Bosentan
Ambrisentan
• 5-phosphodiesterase inhibitors
Sildenafil
Tadalafil
Vardenafil
• Non-pharmacological
Balloon atrial septostomy
Lung Transplant
: available/approved.
70
: available/not approved. Adapted from Morales-Blanhir, et al. 2011.16
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
Table 2. Combined therapy used in Latin America.
Argentina
Brazil
Chile
Colombia
Costa Rica
Cuba
Mexico
Paraguay
Perú
Venezuela
Bosentan+ Sildenafil
Sildenafil+ Iloprost
Iloprost+ Bosentan
Sildenafil+ Treprostinil
Treprostinil+ Bosentan
Treprostinil+ Iloprost
: used. Adapted from Morales-Blanhir, et al. 2011. 16
through a tunneled catheter. This drug improves
symptomatology, exercise capacity and hemodynamics in PAH, it is the only treatment proven to
increase survival in idiopathic PAH, associated
PAH and non-surgical CTEPH in randomized
clinical trials.7,59,60
Treprostinil is a tricyclic benzidine analogue of
epoprostenol; it can be administered intravenously,
subcutaneously, orally and inhaled. Lang, et al.,
performed an long term, open clinical trial where
they observed an improvement in exercise capacity
and symptoms employing SC trepostinil in idiopathic PAH or CTEPH, with a 26 month follow up.7,61
The use of inhaled trepostinil was evaluated in the
TRIUMPH trial (Treprostinil Sodium Inhalation
Used in the Management of Pulmonary Arterial Hypertension) where benefit in PAH patients was observed at 24 months of its administration.62 Another
controlled, randomized trial FREEDOM-C (Oral
Treprostinil for the Treatment of Pulmonary Arterial
Hypertension in Patients on Background Endothelin
Receptor Antagonist and/or Phosphodiesterase Type
5 Inhibitor Therapy) amplified the understanding of
oral dosing and titration of trepostinil.63
Iloprost is a chemically stable prostacyclin analog
that can be administered intravenously or by aerosol. The most used is the inhaled version. In a trial,
63 PAH patients treated with iloprost reported an
85% two year survival, proving that it is a well-tolerated long term therapy.64
Beraprost is a stable oral prostacyclin analog. In a
randomized and controlled trial labeled ALPHABET
(Arterial Pulmonary Hypertension and Beraprost European Trial) in Europe65 and a second in the United
States66 with beraprost at a 80 μg dose, four times a
day, showed an improvement in exercise capacity that
persisted only for 3-6 months, without any evidence
of hemodynamic benefits. In a multicentric trial that
lasted 12 weeks with 46 patients with PAH showed
that a long acting preparation of beraprost (TRK100STP) improved exercise capacity, mPAP and PVR.
It also showed that this product was effective in Japanese patients with PAH.67
Selexipag is an oral, selective prostacyclin receptor agonist. It was evaluated in a double blind, controlled, randomized, phase II trial with 43 PAH
patients. Approximately one third of the patients
were being treated with endothelin inhibitors or
sildenafil as base treatment. The dose of selexipag
was 200 mg twice a day, with increase to maximum
tolerated doses. Decrease in PVR was observed,
when compared with placebo in the seventeenth
week (-30, 3%; p = 0.0045). Additionally, improvement in the 6MW was observed, although this did
not reach statistical significance. When compared
with placebo, selexipag therapy is associated with an
increase in CI. This medication is well-tolerated
with a good safety profile at the expected pharmacological effect.68-70
Endothelin receptor
antagonists
Activation of the endothelin (ET) system has been
demonstrated in both plasma and lung tissue of
PAH patients.
Bosentan is an oral active dual endothelin-A and
endothelin-B receptor antagonist (ERA). It has been
evaluated in PAH (idiopathic, associated with connective tissue disease and Eisenmenger’s syndrome)
in randomized clinical trials BREATHE-1,2,5:
(Bosentan Randomized Trial of Endothelin Antagonist Therapy-1,2,5) and EARLY (Endothelin Antagonist trial in Mildly Symptomatic PAH patients)
that showed improvement in exercise capacity, functional class, hemodynamics, echocardiographic
variables and time to clinical worsening.7,56 In a
registry with 528 patients, distributed in 15 referral
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
71
centers in Australia, from 2004-2007, it was demonstrated that treatment with bosentan improved
prognosis in idiopathic PAH and connective tissue
disease-associated PAH.71. In multiple trials, there
was a 10% rise in hepatic aminotransferases
enzymes; this is why liver function tests must be
done at least once a month.56
Ambrisentan is a non-sulfonamide, propanoic
acid-class, ERA that is selective for the endothelin-A
receptor. Its usage was evaluated in two randomized, controlled clinical trials ARIES 1-2: (Ambrisentan in Pulmonary Arterial Hypertension 1 and
2), which demonstrated efficacy in symptomatology,
exercise capacity, hemodynamics and time to clinical
worsening.72 In these patients liver function tests
have to be done once a month.
Macitentan is a new dual ERA in clinical development for PAH. A phase 1 clinical trial, compared
pharmacokinetics and safety of macitentan in
healthy Caucasian and Japanese subjects; it also
compared difference between genders. The study
showed no significant clinical difference with adverse effects, laboratory values, EKG and vital signs
between the two groups. Additionally, they proved
that it was not necessary to adjust the dose of macitentan based on gender or ethnicity.73
Pulmonary fibrosis is a progressive and fatal disease. A double-blind, randomized, placebo-controlled,
multicenter, parallel group study to evaluate the efficacy, safety, and tolerability of macitentan in patients with idiopathic pulmonary fibrosis
(NCT00903331) did not demonstrate that macitentan positively affects the forced vital capacity (FVC)
in comparison with placebo in patients with idiopathic pulmonary fibrosis.74
In another multicenter, double blinded, randomized controlled-placebo trial called SERAPHIN
(Study with an Endothelin Receptor Antagonist in
Pulmonary Arterial Hypertension to Improve Clinical Outcome) showed that macitentan significantly
reduced mortality in PAH. 75
Phosphodiesterase-5 inhibitors
The benefit of phosphodiesterase-5 inhibitors
(PDE-5) in vascular remodeling and pulmonary vasodilation is well known.
Sildenafil is an orally active PDE-5 selective inhibitor. Several non-controlled trials have described
favorable effects of sildenafil in idiopathic PAH, connective tissue or congenital heart disease associated
PAH and CTEPH. A randomized, controlled trial
SUPER-1 (The Sildenafil Use in Pulmonary Hyper-
72
tension-1), showed that 278 patients with PAH
treated with sildenafil 20, 40 and 80 mg, three times
a day (TID), had a favorable effect in: exercise capacity (increasing 50m in the 6MW), symptoms, hemodynamics and quality of life.76 The dose approved
is 20 mg TID. Once the SUPER-1 TRIAL concluded,
259 of the 277 patients were enrolled in the SUPER2, an open, non-controlled extension. These 2 trials
proved that long treatment (> 3 years) with sildenafil as a monotherapy improved WHO-FC and 6MW
in patients with PAH.77
In patients with chronic to obstructive pulmonary disease (COPD) associated PH, sildenafil improved hemodynamic parameters at rest and during
exercise. This effect is accompanied by the inhibition
of the hypoxic vasoconstriction and deterioration of
arterial oxygenation at rest; this is why in COPD
associated PAH arterial blood gas monitoring is necessary.78
Tadalafil is a selective inhibitor of PDE-5, administered once a day. It was studied, in a controlled,
randomized trial, called PHIRST (Tadalafil in the
Treatment of Pulmonary Arterial Hypertension),
which included 405 patients with PAH treated with
tadalafil doses of 5, 10, 20 or 40 mg, once a day.
They observed positive results in: exercise capacity,
symptoms, hemodynamics and time to clinical deterioration with the highest dose. This trial concluded
that monotherapy with tadalafil 40 mg, favors clinical improvement in these patients.79
Vardenafil is a selective inhibitor of PDE-5. Jing,
et al., in an open, multicentric trial with 45 patients
with PAH, treated with vardenafil 5 mg, once a day,
during 4 weeks and then 5 mg twice a day, showed
that therapy was well tolerated, it improved 6MW,
WHO-FC and hemodynamic parameters.80
Riociguat is a soluble guanylate cyclase activator that produces vasodilation and stimulates endogenous nitric oxide mediated vasodilation. Two
clinical trials have studied riociguat, PATENT-1
(Pulmonary Arterial Hypertension Soluble Guanilate Cyclase-Stimulater trial 1)81 and CHEST-1
(Chronic Thromboembolic Pulmonary Hypertension
Guanilate Cyclase-Stimulater trial 1).82 In the first
trial, 443 patients with PAH were treated with riociguat during 12 weeks, it showed improvement in
the 6MW distance covered and PVR. The second
trial, with 261 patients with CTEPH observed improvement in the same parameters though 16
weeks. Riociguat would be the first non-surgical
therapy approved for CTEPH and an additional option in PAH, where it seems to be safe and well tolerated.
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
Hoeper, et al., administered riociguat, in a nonrandomized, open trial with 13 cases of idiopathic
pulmonary fibrosis (IPF) associated PAH, 5 cases of
unspecific interstitial pneumonia, 3 cases of sarcoidosis and 1 case of scleroderma, observing hemodynamic improvement at 12 weeks and an increase
in the 6MW, but no change in WHO-FC or clinical
improvement. Adverse effects were lower extremity
edema, dyspepsia and headaches.83
In another double blinded, randomized trial, the
effect of riociguat was evaluated in 201 patients
with PH due to LV systolic dysfunction; although
the primary endpoint of the study was not met, riociguat was well tolerated and improved the cardiac
index, and systemic and PVR.84,85
COMBINATION THERAPY
This is an attractive and logic alternative in PAH
patients. It is directed to those patients who have a
poor response to initial monotherapy CR:I-LE:A and
WHO-FC III and IV CR:IIb-LE:C. The severity of
disease and increase in the number of available medications, invite the exploration of combining different mechanisms of action with the purpose of
optimizing clinical benefit and decreasing adverse effects. The two proposals are:
• Start with combination therapy, or
• Add a new medication to the patients existing
treatment regimen (sequential combination).86
Multiple studies suggest that combination therapy is effective.87-92 Humbert, et al., evaluated the
administration of bosentan and epoprostenol in 33
patients with PAH WHO-FC III and IV and
observed hemodynamic improvement but had no
statistical significance. 87 McLaughlin, et al.,
showed in a study with 67 patients with PAH the
benefits of adding inhaled iloprost in patients who
were using bosentan, observing an improvement
in WHO-FC and 6MW. 88 The addition of bosentan
to patients who were using sildenafil (or vice versa) has also been studied. 89,90 The addition of
sildenafil to epoprostenol was described in a 267
PAH patient study that observed improvement in:
exercise capacity, hemodynamics and quality of
life; but not in the dyspnea Borg scale. 91 Another
drug added to bosentan and sildenafil is inhaled
trepostinil. In a study with 235 PAH patients,
WHO-FC III and IV showed an improvement in
quality of life and exercise capacity with trepostinil and bosentan or sildenafil combination. 92
Lastly, the addition of tadalafil in patients who
were receiving bosentan did not show conclusive
results or benefits.79,93
FUTURE MEDICAL THERAPIES
New therapeutic agents are aimed at reversing
sustained or abnormal vasoconstriction and/or at
stopping or reversing abnormal cell growth and
abnormal extracellular matrix protein deposition.
Some of these promising therapies include: vasodilator peptides (vasoactive intestinal peptide), gene
therapy, tyrosine kinase inhibitors and growth
factor inhibitors (imatinib, gefitinib, erlotinib y
patinib).94-96
Vasoactive intestinal peptide (VIP) is a potent
pulmonary and systemic vasodilator. It is administered via inhalation in PAH. Rhodes, et al., in a
case series of 8 idiopathic PAH patients, treated
with inhaled VIP at a dose of 200 μg for 3 months,
observed significant changes in mPAP < 13 mmHg,
cardiac index > 1.7 L/min, PVR < ~50% and 6MW
> 113 m. VIP should be considered as a future alternative in PAH pharmacotherapy.94
Hereditary PAH is associated to BMPR2 mutation. This has raised the idea of utilizing gene therapy to replace the missing gene and possibly serve as
a permanent cure of the disease. No clinical trials
have shown positive results on this therapeutic modalito.97
Tyrosine kinase inhibitors, specifically platelet
derived growth factors (PDGF) have shown to be
potent vasodilators, decreasing excessive vasoconstriction and smooth muscle proliferation. Several
case reports suggest that terminal phase PAH patients can benefit from PDGF inhibitors, e.g. imatinib.96
Other pathways currently being investigated:
Rho kinase (ROCK) inhibitors (fasudil), endothelial nitric oxide synthase coupling agents (cicletanine), multikinase inhibitors (sorafenib), elastase
inhibitors, metabolic modulators (dichloroacetate), survivin inhibitors, peroxisome proliferatoractivated receptor gamma Inhibitors. (PPAR γ)
and 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)
reductase inhibitors. The majority of these medications are in the initial phases of investigation
in PAH.98
SURGICAL TREATMENTS
Indicated in PAH when the response to medical
therapy in not adequate. It is constituted by two
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
73
Table 3. Medical and patient societies in Latin America.
Society
Location (city, country)
Hipertensión Pulmonar Argentina Asociación Civil (HIPUA)
Asociación Brasileña de amigos y Familiares de portadores de Hipertensión Pulmonar
Federación Boliviana de Hipertensión Pulmonar
Organización de Hipertensión Pulmonar en Chile
Fundación Colombiana de Hipertensión Pulmonar (FCHP)
Asociación de Afectados de Hipertensión Pulmonar
Asociación Nacional de Hipertensión Pulmonar (ANHP)
Fundación Contra la Hipertensión Pulmonar
Grupo de Apoyo Hispano para Pacientes de Hipertensión Pulmonar de Nueva York
Sociedad Latina de Hipertensión Pulmonar
Pulmonary Hypertension Association
Grupo de Apoyo para Pacientes de Hipertensión Pulmonar en Español
Asociación Mexicana de Hipertensión Pulmonar
Grupo de Pacientes con Hipertensión Pulmonar A.C
Fundación de Apoyo para la Hipertensión Pulmonar del Sureste
Fundación de Pacientes con Hipertensión Pulmonar de Panamá
Asociación Paraguaya de Escleroderma y Enfermedades Autoinmunes
Federación Paraguaya de Hipertensión Pulmonar
Asociación Médica Peruana de Hipertensión Pulmonar
Grupo de apoyo para pacientes con Hipertensión Pulmonar en Puerto Rico
Grupo de apoyo para pacientes con Hipertensión Pulmonar en República Dominicana
Grupo de Apoyo para Pacientes con Hipertensión Pulmonar en Uruguay
Fundación Venezolana de Hipertensión Pulmonar
Buenos Aires, Argentina
Sao Paulo, Brazil
La Paz, Bolivia
Santiago, Chile
Santa Fé de Antioquía, Colombia
Barcelona, Spain
Madrid, Spain
Madrid, Spain
New York, USA
Pembroke Pines, FL, USA
Silver Spring, MD, USA
South Florida, FL, USA
Mexico City, México
Mexico City, México
Mérida, Yucatán, México
Panamá City, Panamá
Paraguay
Asunción, Paraguay
Lima, Perú
San Juan, Puerto Rico, USA
Santo Domingo, Dominican Republic
Montevideo, Uruguay
Caracas, Venezuela
Adapted from Morales-Blanhir, et al. 2011.16
techniques: balloon atrial septostomy and lung or
heart-lung transplantation.
Ballon atrial septostomy is a palliative treatment
in PAH patients. CR: IIa-LE: C in the majority of
cases, this intervention is practiced in patients
where there is therapeutic failure to the available
medical treatments or as a palliative bridge towards
lung transplantation. Which explains the high mortality rates 5-15% 56. Law, et al., in a study with 43
PAH patients, showed that septostomy provides improvement in symptomatology and hemodynamics
(cardiac index and RAP).99
Heart-lung or lung transplantation in PAH has
been evaluated only in prospective, non-controlled
trials, due to the fact that formal controlled and
randomized trials are not considered ethical in the
absence of alternative treatment options. Survival
rates in transplanted patients are similar in heartlung and unilateral or bilateral lung transplantation
in PAH CR:I-LE:C.56 However, multiple transplant
centers prefer to do bilateral lung transplantation.
In a retrospective study with 219 patients divided
according to their PH classification group (147
group I, 24 group III, 20 group IV and 20 group V);
67 patients received lung transplantation and 152
74
heart-lung transplantation. This study proved that
there is good long term survival rate in terminal
phase PH patients who receive a lung or heart-lung
transplant. The results show preference in performing a heart-lung transplant in patients with RV failure or congenital shunts (pulmonary or systemic).
Death due to bronchiolitis obliterans was less common in lung-heart than lung transplantations.100
CURRENT SITUATION
In Latin America, there is a better organization
of medical and patient PH societies (Table 3).
Taking México as an example, there are several institutions: Rare Disease Mexican Federation (FEMEXER), Project “Pide un deseo” México and
others, who took as their main objective to prioritize and raise awareness of rare diseases. Together
they convinced the Mexican government to publish
a decree in the Official Paper of the Mexican Federation, dated 01/30/2012, where the Health Secretary
had to promote the availability of orphan drugs and
broadcast recommendations to all health institutions to investigate and develop medications with effective potential.
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78
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Correspondence and reprint request:
Dr. Jaime Eduardo Morales-Blanhir
Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán
Vasco de Quiroga, Núm. 15
Col. Sección XVI
14080, México, D.F.
E-mail: [email protected]
Received: September 26, 2013.
Accepted: December 17, 2013.
Morales-Blanhir JE, et al. Pulmonary arterial hypertension. Rev Invest Clin 2014; 66 (1): 65-78