Pulmonary HyPertension: newer insigHts
4:4 S Bhandari, PS Sandhu, New Delhi
Most practicing cardiologists see patients with pulmonary hypertension (PH) on a regular basis. The
explosion in knowledge of and treatment for PH over the past decade obligates cardiologists to be
more cognizant of this disorder.
PH has been defined as a resting mean pulmonary arterial pressure (mPAP) >25 mm Hg, or >30 mm
Hg with exercise. The subgroup of PH known as pulmonary arterial hypertension (PAH) adds the
criterion that the pulmonary arterial wedge pressure must be ≤15 mm Hg.1
The clinical classification of PH has gone through a series of changes since the first version was
proposed in 1973 at the first international conference on primary pulmonary hypertension endorsed by
the WHO (Table 1).2 The initial classification designated only 2 categories, PPH or secondary PH. 25
years later, the 2nd World Symposium on PAH was held in Evian, France. The “Evian classification”
attempted to create categories of PH that shared pathologic and clinical features as well as similar
therapeutic options 3
The 3rd World Symposium on PAH was held in Venice, Italy, 5 years after the Evian conference. At
this conference modest changes were made. The most notable change was to abandon the term PPH in
favor of idiopathic pulmonary arterial hypertension (IPAH); familial PAH if there is a family history
of PAH; or associated PAH if another cause, such as CTD or HIV, is present. The term “secondary
PH” was abandoned since it did not help with diagnosis or in directing treatment.4
During the 4th World Symposium on PH held in 2008 in Dana Point, California, the general philosophy
and organization of the Evian-Venice classifications was maintained, but modified it to clarify some
areas that were unclear.
PAThOPhySIOLOgy OF Ph
Different pathological5,6,8–10 features characterize the diverse clinical PH groups.
• Group 1, PAH: The increase in PVR is related to different mechanisms, including vasoconstric-
tion, proliferative and obstructive remodeling of the pulmonary vessel wall, inflammation, and
• Group 1′: includes mainly PVOD which involves septal veins and pre-septal venules with oc-
clusive fibrotic lesions, venous muscularization, capillary proliferation (patchy), pulmonary
oedema, occult alveolar haemorrhage, lymphatic dilatation and lymph node enlargement (vas-
cular transformation of the sinus), and inflammatory infiltrates.
• Group 2, PH due to left heart disease.
• Group 3, PH due to lung diseases and/or hypoxia. The pathophysiological mechanisms involved
in this setting are hypoxic vasoconstriction, mechanical stress of hyperinflated lungs, loss of
capillaries, and inflammation.
Medicine Update 2012 Vol. 22
Table 1 Updated clinical classification of Ph (Dana Point, • Group 5, PH with unclear and/or multifactorial mecha-
1 Pulmonary arterial hypertension (PAH)
NATURAL hISTORy AND PROgNOSTIC FACTORS
The natural history of IPAH was well described by the NIH
registry in 1985 before the availability of any disease-specific
therapy.11 The median survival was 2.8 years, with 1, 3, and
1.2.2 ALK1, endoglin (with or without hereditary haemorrhagic 5-year survival rates of 68%, 48%, and 34%, respectively.12
Associated conditions influence outcomes: Patients with CTD
and HIV-associated PAH tend to have a worse prognosis,
1.3 Drugs and toxins induced whereas those with congenital heart disease–associated PAH
1.4 Associated with (APAH) tend to have a better prognosis.
1.4.1 Connective tissue diseases(CTD)
Important prognostic indicators in PAH include symptoms,
1.4.2 HIV infection exercise endurance, and hemodynamics.13Most of these
1.4.3 Portal hypertension prognostic variables are related to RV function. In the NIH
1.4.4 Congenital heart disease registry, the median survival among patients presenting with
1.4.5 Schistosomiasis class I and II symptoms was ~ 6 years versus 2.5 years for patients
1.4.6 Chronic haemolytic anaemia with class III symptoms and just 6 months for patients who
1.5 Persistent pulmonary hypertension of the newborn
presented with class IV symptoms.12 Two large retrospective
series have confirmed the importance of functional class
1′ Pulmonary veno-occlusive disease and/or pulmonary capillary
haemangiomatosis as a prognostic variable, even during treatment.14,15 Among
IPAH patients treated with epoprostenol, prognosis was worse
2 Pulmonary hypertension due to left heart disease
for patients who commenced therapy with more advanced
2.1 Systolic dysfunction
symptoms. Moreover, in both series, patients who improved
2.2 Diastolic dysfunction to class I or II status after 3 to 17 months of epoprostenol
2.3 Valvular disease therapy had a better prognosis than patients who remained
3 Pulmonary hypertension due to lung diseases and/or hypoxia in class III or IV.
3.1 Chronic obstructive pulmonary disease Exercise tolerance in PAH is commonly assessed by means
3.2 Interstitial lung disease of the 6-minute-walk distance (6MWD). In one of the first
3.3 Other pulmonary diseases with mixed restrictive and obstructive controlled trials, a 6MWD of <150 m was associated with a
pattern very poor prognosis. 16 In a series of 178 IPAH patients treated
3.4 Sleep-disordered breathing with epoprostenol, those who walked further than the median
3.5 Alveolar hypoventilation disorders value of 380 m after 3 months of therapy had a better prognosis
3.6 Chronic exposure to high altitude than those who did not.16
3.7 Developmental abnormalities PROgReSS OF meDICAL TReATmeNT IN PUL-
4 Chronic thromboembolic pulmonary hypertension mONARy ARTeRIAL hyPeRTeNSION
5 PH with unclear and/or multifactorial mechanisms In 1891, Ernst von Romberg, a German physician, described
5.1 Haematological disorders: myeloproliferative disorders, splenec- an autopsy subject as having “pulmonary vascular sclerosis”;
however, it is only since 1995 with the introduction of
5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell his- epoprostenol that disease-specific targeted medical therapies
tiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vascu-
for PAH have become available. Furthermore, significant
advances in the treatment of PAH have occurred during the
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease,
thyroid disorders past 15 years. Currently 9 medical therapies have received
regulatory approval. These agents target the prostacyclin
5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic re-
nal failure on dialysis pathway, the nitric oxide pathway, and the endothelin pathway.
Combination trials have demonstrated additive or synergistic
ALK-1 = activin receptor-like kinase 1; BMPR2 = bone morphogenetic pro-
tein receptor 2, HIV = human immunodeficiency virus. benefit by targeting 2 or all 3 of these pathways (Figs. 1 and 2).
• Group 4, CTEPH: non-resolution of acute embolic
masses which later undergo fibrosis leading to mechani- Diuretics role has been limited to patients manifesting RV
cal obstruction of pulmonary arteries. failure. However, patients with advanced PAH can have
increased left ventricular filling pressures that contribute
Pulmonary Hypertension: Newer Insights
its vasodilator and antithrombotic effects. Patients may have
AIR Sildenafil STRIDE2 ARIES
a reduction in PVR of ≥50%, even if no acute hemodynamic
Epoprostenol BREATHE1 BREATHE2
effects are noted. Epoprostenol is administered through
Epoprostenol SERAPH TRIUMPH
STRIDE1 BREATHE5 PACES
a central venous catheter that is surgically implanted and
delivered by an ambulatory infusion system.
1990 1996 2000 ‘01 ’02 ‘03 ’04 ‘05 ’06 ‘08 ’09 ‘10
Most complications are due to the delivery system and include
Monotherapy catheter-related infections and temporary interruption of the
Monotherapy and/or sequential combination infusion because of pump malfunction, which causes rebound
pulmonary hypertension. Side effects related to epoprostenol
Colour code identifies the design of the study: monotherapy (black): in- are flushing, headache, nausea, diarrhea, and a jaw discomfort
vestigational drug vs. placebo in patients naive for PAH approved drugs.
that occurs with eating. In most patients, these symptoms are
Monotherapy and/or sequential combination (red): investigational drug vs.
placebo in patients either naive for, or treated with PAH approved drugs. minimal and well tolerated.
Upfront combination (light blue): single drug vs. combination of two drugs
in patients naive for pulmonary arterial hypertension approved drugs.
The experience with epoprostenol in patients with IPAH
for more than 10 years has been reported by two large
Fig. 1: Time-course of 25 published RCT in pulmonary arterial centers.14,15 Survival rates markedly improved; predictors of
survival included NYHA class, exercise tolerance, and acute
vasodilator responsiveness. Both studies provided important
to the symptoms of dyspnea and orthopnea, which can be
data for identifying patients who would do well over the
relieved with diuretics.
long term, versus those in whom transplantation should be
Because hypoxemia is a potent pulmonary vasoconstrictor, considered.
oxygen supplementation is given to maintain SPO2 > 90%.
Treprostinil is a stable prostacyclin analogue that has
Anticoagulants The evidence for favorable effects of oral pharmacological actions similar to those of epoprostenol,
anticoagulant treatment is based on retrospective analyses from but differs in that it is chemically stable at room temperature
7 studies, of which 5 were positive and 2 were negative.18,20,22 and neutral pH and has a longer half-life. It is administered
The survival of anticoagulated patients selected on the basis through continuous S/C infusion. In a large RCT in patients
of clinical judgment was improved from 21% to 49%. Most with PH, it was effective in increasing 6MWD, decreasing
experts recommend warfarin anticoagulation targeted to an dyspnea, and hemodynamics.25
INR of 2.0 to 3.0.
Iloprost, an inhalational analogue of prostacyclin. In RCT,
Short-term IV digoxin in IPAH produces a modest increase inhaled iloprost was shown to have an acute effect on
in cardiac output and a significant reduction in circulating hemodynamics similar to those of inhaled nitric oxide and
norepinephrine21; no data is available on the effects of long- when given chronically, causes improvement in 6MWD, and
term treatment. Therefore, the use is based primarily on the in hemodynamics.26 Because of the short half-life of iloprost,
judgment of the physician. however, it requires frequent (up to 12/day) inhalations.
CCBs Favorable clinical and prognostic effects of high doses Beraprost is an orally active prostacyclin analogue that has
of oral CCB drugs in acutely vasoreactive patients with been evaluated in RCT trials in patients with PAH. In one
IPAH have been shown in single-center, nonrandomized, large European trial (ALPHABET study), beraprost improved
uncontrolled studies.17, 22 exercise capacity and symptoms over a 12-week period but
Acute vasodilator testing is recommended for all PAH had no significant effect on hemodynamics or functional
patients, even though patients with IPAH and anorexigen class. A similar trial conducted in the United States, however,
induced PAH are more likely to respond. Empirical treatment showed similar efficacy at 12 weeks, only to document the
with CCBs without a positive response with acute vasodilator loss of effectiveness over 1 year.27 At present, beraprost is only
testing using either inhaled nitric oxide or IV epoprostenol is approved for use in Japan.
contraindicated.23 eNDOTheLIN ReCePTOR BLOCkeRS (eRA)
SyNTheTIC PROSTACyCLIN AND PROSTACyC- ET-1 exerts vasoconstrictor and mitogenic effects and is
LIN ANALOgUeS activated in PAH. Three endothelin receptor blockers have
Prostacyclins have been found to be effective in the therapy been approved for PAH. Although there have never been direct
of PAH.15 Continuous IV infusion of epoprostenol has been comparative trials, all three appear to have similar efficacy.28
shown in RCT to improve quality of life and symptoms related Bosentan is a non-selective ET receptor blocker. 9 RCTs
to PH. The long-term effects of epoprostenol in PH include using 1 of 3 ERAs as monotherapy have been performed
Medicine Update 2012 Vol. 22
Vasodilator Therapies Antiplatelet Therapies
Oxygen Prostacyclin analogues
Calcium-channel blockers Nitric oxide donors
Endothelin-receptor antagonists L-arginine
Brain natriuretic peptide Phosphodiesterase inhibitors Anticoagulant
Calcitonin gene-related peptide Prostacyclin synthase Therapies
Prostacyclin analogues Smooth
Nitric oxide donors muscle cells Platelets Fibrin
Nitric oxide donors
Nitric oxide donors
Fig. 2 : Therapeutic Approaches to Pulmonary Hypertension 24
in PAH patients, bosentan was evaluated in 4 RCTs in PAH receptor blocker that can be given once daily at a 100 mg
patients,29-31 including 1 RCT performed in a cohort of patients dose. It has been assessed in PAH patients in 2 RCTs, both of
with the Eisenmenger syndrome31 and 1 RCT performed in which demonstrated improvement in exercise capacity and
a cohort of patients with only mildly symptomatic PAH.32 hemodynamic status.33,34
Overall, bosentan improved exercise capacity, functional
Ambrisentan is an orally active ETA-selective endothelin
class, hemodynamic status, echocardiographic and Doppler
receptor blocker that can be given once daily at a 5-mg dose,
variables, and time to clinical worsening. The approved
which can be increased to 10 mg if the drug is well tolerated. It
dosage of bosentan is 125 mg twice daily.
has been evaluated in RCTs.35 Results showed improvements
Sitaxsentan is an orally active ETA-selective endothelin
Pulmonary Hypertension: Newer Insights
ALgORIThm FOR The meDICAL TReATmeNT OF PAh.42
Oral anticoagulants (E/B)-IPAH/HPAH Supportive therapy and general measures Avoid excessive physical exertion (E/A)
Diuretics (E/A) Birth control (E/A)
Oxygen* (E/A) Psychological and social support (E/C)
Digoxin (E/C) Expert referral (E/A) Infection prevention (E/A)
Supervised rehabilitation (E/B)
Acute vasoreactivity test (A for IPAH)
(E/C for APAH)
WHO Class I-IV Strength of
Amlodipine, diltiazem, Recommendation WHO Class II WHO Class III WHO Class IV
nifedipine (B) Ambrisentan, Bosentan, Ambrisentan, Bosentan, Epoprostenol IV
A Sildenafil Epoprostenol IV, Iloprost inh,
Sitaxsentan, Tadalafil Sitaxsentan, Tadalafil, Iloprost inh
Sustained response Treprostinil SC
(WHO I-II) C Beraprost Treprostinil SC
Iloprost IV, Treprostinil IV Iloprost IV, Treprostinil IV
E/B Initial combination therapy (see
YES NO Sildenafil, Sitaxsentan, Tadalafil
Not approved Treprostinil inh+ Treprostinil inh+
INADEQUATE CLINICAL RESPONSE
nifedipine (B) Sequential combination therapy
Prostanoids INADEQUATE CLINICAL RESPONSE
+ (B) + (B)
Atrial septostomy (E/B) and/or
PDE-5 I + (B) ERA lung transplant (E/A)
in exercise capacity and clinical events that seem similar to In the pivotal tadalafil RCT, ~50% of the patients had oral
the results observed with the other 2 ERAs. tadalafil added to background oral bosentan; it improved
exercise capacity, hemodynamic status, and clinical
On the basis of the results of RCTs using ERAs, the incidence
events. Inhaled treprostinil has also been studied as add-on
of elevated hepatic transaminases >3 times the upper limit of
therapy to either background bosentan or sildenafil; in both
normal seems to be ~10, 4, 2% with bosentan, sitaxsentan,
combinations, the addition of inhaled treprostinil improved
and ambrisentan respectively. They have interactions with
exercise capacity.39 These studies support the efficacy of
warfarin that require careful monitoring of the INR and dose
combination treatment in patients who remain symptomatic
adjustments when used together.
on monotherapy. The optimal combination on the basis of
COmBINATION TheRAPy overall risk-benefit considerations remains unknown.
Combination treatment has been evaluated to address the eARLy INTeRveNTION
multiple pathobiologic mechanisms of PH. The combination
For functional class II or III patients, the role of early
of oral bosentan and IV epoprostenol was investigated in
aggressive intervention, either as monotherapy or in
1 small study, with inconclusive results.35,36The addition of
conjunction with either a PDE-5 inhibitor and/or an ERA,
inhaled iloprost to background oral bosentan demonstrated
remains unknown. Although the first RCTs in PAH focused
improved hemodynamic status and clinical events in 1 RCT40;
primarily on functional class III and IV patients, results from
however, these results were not confirmed in an open trial.37
a more recent RCT evaluating the efficacy of bosentan in only
In another study, the addition of oral sildenafil to background
mildly symptomatic PAH patients support early intervention.35
IV epoprostenol demonstrated improved exercise capacity,
In addition, prespecified subgroup analyses of the sildenafil,
hemodynamic status, and clinical events; furthermore, the
tadalafil, and ambrisentan RCTs did not show any significant
addition of oral sildenafil to background IV epoprostenol
differences in the therapeutic efficacy of these drugs between
increased survival versus IV epoprostenol alone.38
patients in WHO functional classes II and III.35
Medicine Update 2012 Vol. 22
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which is based on experimental and clinical observations
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