Pulmonary hypertension

1. Pulmonary hypertension
& its management
DR DIPAK PATADE
DMH.

2. PULMONARY CIRCULATION
Blood volume of the lungs is about 450 ml .(about 9% of the total blood volume).
Lungs serve as a blood reservoir.
Cardiac pathology may shift blood from the systemic circulation to the pulmonary circulation EG
,Failure of the left side of the heart Mitral stenosis or regurgitation.
Two Circulatory Systems of the Lung:
1. High pressure low flow circulation : that supplies systemic arterial blood supplied mostly by
the bronchial arteries.
2. Low pressure high flow circulation: that supplies venous blood to the alveolar capillaries
where oxygen is added and carbon dioxide is removed.
Pulmonary Vessels- pulmonary artery and its branches are thin and distensible and exhibit large
compliance; this allows the pulmonary arteries to accommodate the stroke volume output of the
right ventricle.
Bronchial Vessels- bronchial arterial blood is oxygenated and supplies the supporting tissues of
the lungs; empties into the pulmonary veins and enters into the left atrium.

3. PULMONARY CIRCULATION
 Pulmonary vascular resistance (PVR) is a measure of the impedance to flow in the
pulmonary vasculature.
 PVR Depends on pulmonary artery pressure, left atrial pressure and the cardiac
output.
 Normal pulmonary artery pressure= 25/8 mmHg.
 Normal mean pulmonary artery pressure= 15+/-3mmHg.
 Pulmonary venous pressure is about = 8 mmHg.

4. PAP
PAP = (CO x PVR) + PVP
where ,
CO = cardiac output,
PVR = pulmonary vascular resistance, and
PVP = pulmonary venous pressure(same as left atrial pressure)
Therefore, increases in CO, PVR or PVP will lead to increases in PAP.
the pressure gradient driving flow through the pulmonary circulation is rather
small at about 7 mmHg (mean pulmonary arterial minus venous pressures).
This is a much lower driving pressure than the systemic circulation where the
arterial-venous pressure gradient is about 90 mmHg.
Although the blood flow through the pulmonary circulation is essentially the same
as the blood flow through the systemic circulation, the pulmonary vascular
resistance is ten- to fifteen-fold lower than the systemic vascular resistance.

5. OVERVIEW OF PRESSURES

6. Pressure curves of right ventricle

7. Pulmonary hypertension
 A complex ,multidisciplinary disorder.
 Pulmonary hypertension (PH) is an abnormal- increase in mean PAP
(mPAP) of 25 mmHg or more at rest or Increase in mPAP >30 mmhg
during exercise as assessed by RHC.
 It is a feature of advanced disease.
 The pulmonary artery pressure and pulmonary vascular resistance
progressively rises, leading to right heart failure and death.
 Over the years, improvement in understanding the pathogenesis has
resulted in the development of targeted approaches to the treatment of
PH.
 Survival advantage has also been shown with some of the pharmacologic
agents.

8. types
Pre capillary PH:
 mPAP ≥ 25 mmHg ,PCWP ≤15 mmHg ,PVR >3 wood units
 It comprises- group I (PAH) , group III ( sec to lung disease),group V( unclear
or multifactorial origin) patients .
Post capillary PH:
 mPAP ≥ 25 mmhg ,PCWP ≥ 15 mmHg
 It comprises- group II ( left heart disease ) , group IV (CTEPH) and some group
V.
 DPG= dPAP-mean PCWP
 DPG> 7 : isolated Post capillary PH
 DPG <7 : both precapillary and postcapillary PH

9. Classification(2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension
4th World Symposium on Pulmonary Hypertension held in Dana Point, California, in 2008 .

10. Where is the disease ?

11. Pathology
 PAH-
 early distal pulmonary arteries involvement (<500m)-muscular arteries ,rather
than elastic arteries. medial hypertrophy, intimal proliferation , fibrotic changes
,adventitial thickening, perivascular mononuclear cell infiltrates ,plexiform
lesions ,thrombotic lesions.
 Pulmonary veins are spared in PAH.
 In PVOD –septal veins and venules, fibrotic bands , venous musculisation,
alveolar hemorrhage ,lymphatic dilatation with inflammatory infiltrates.
 PH due to Left heart disease :
 Enlarged and thickened pulmonary veins, pulmonary capillary dilatation ,
interstitial edema ,alveolar hemorrhage , lymphatic vessel enlargement .Distal
pulmonary artery late involved by medial hypertrophy and intimal proliferation.

12. Pathology
 PH sec to lung diseases : Distal pulmonary arteries may be affected late in
Group 3 - PH due to lung diseases and/or hypoxia.
 medial hypertrophy and intimal obstructive proliferation of the distal
pulmonary arteries. A variable degree of destruction of the vascular bed in
emphysematous or fibrotic areas may also be present.
 CTEPH: organized thrombi tightly adherent to pulmonary artery medial
layer in elastic pulmonary arteries and has replaced the intima, completely
occlude the lumen or forming webs , variable stenosis , bands. Extensive
collateral development is seen around the occluded segments. Non-
resolution of acute embolic masses which later undergo fibrosis leading to
mechanical obstruction of pulmonary arteries. Pulmonary
thromboembolism or in situ thrombosis may be initiated or aggravated by
abnormalities in either the clotting cascade, endothelial cells, or platelets.
 Group V : multifactorial causes are involved,

13. Hereditary PAH

14. Hereditary PAH

15. Pathogenesis

18. Molecular Pathways involved

19. Molecular Pathways involved
 Prostacyclin: Prostacyclin is a potent vasodilator, inhibits platelet activation,
and has antiproliferative properties
 Prostacyclin synthase is decreased in the pulmonary arteries in PAH.
 Endothelin-1: Endothelin-1 (ET-1) is a potent vasoconstrictor and stimulates
PASMC proliferation.
 Plasma levels of ET-1 are increased in PAH and clearance is reduced.
 Nitric Oxide: Nitric oxide (NO) is a vasodilator and inhibitor of platelet
activation and vascular smooth-muscle cell proliferation.
 Once formed, the effects of NO are largely mediated by cGMP which is rapidly
inactivated by PDE, especially the PDE-5 isoenzymes.

20. Endothelial normal function

21. Endothelial dysfunction

22. PAH(formerly PPH,IPAH)
1.IPAH:
 prevalence: 15 to 50 cases per 10,00,000 population.
 Unknown cause ,sporadic ,no familial tansfer
 MC group I cause nowadays
 F:M= 2:1 as per NIH, 4:1 as per REVEAL
 Mean age of presentation: 37 years as per NIH , 50 years as per REVEAL
2. hereditary: BMPR-2 gene mutations in involed in TGF b2 signaling
pathway , EIF2AK4 gene mutation for PVOD, other:BMPR 1B,CAV 1,SAMD9
 Autosomal dominant trait is common
 Anticipation is also seen

23. 3.Drug and toxin induced PAH
(2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension)

24. PAH(formerly PPH,IPAH)
4. 1associated with connective tissue diseases
 Prevalence in Scleroderma patients : 8 to 12 %
 Clinical evlaution ,ECHO and PFT are must for screening
 Poor prognosis despite of treatment : 3 yrs survival is 56% as per French registry
4.2 Associated with HIV-
 incidence is independent of CD4 count but better prognosis with counts >200
cells/mcl
4.3 Associated with Portal Hypertension:
 Prevalence : 2 to 6%
 Pre liver transplant PH >35 mmhg –increases mortality and PH >45 mmhg is
absolute contraindication for liver transplantation.
4.4 associated with schistosomiasis
 South America , sub Saharan Africa
 Prevalence :5% of patients

25. 4.4 associated with congenital heart diseases

26. Clinical diagnosis
SYMPTOMS
 Exertional dyspnea, chest discomfort
 Easy fatigability ,Lethargy
 Light headedness
 Syncope with exertion
 Dry Cough
 Hemoptysis
 Hoarseness of voice
 Lower extremity edema , ascites
 Delay in diagnosis: average 2 years esp OSA, COPD and young people

28. Physical signs

29. Physical signs

30. Functional class in PH

31. ECG-
 Right ventricular Hypetrophy often with strain
 Right axis deviation
 RAE

32. CXR

33. ECHOCARDIOGRAPHY

34. ECHOCARDIOGRAPHY

35. ECHOCARDIOGRAPHY
 To diagnose Pulmonary hypertension (PH) peak tricuspid regurgitation
(TR) velocity is used.
 With help of simplified Bernoulli equation peak pressure gradient of
tricuspid regurgitation is calculated
 Peak pressure gradient of tricuspid regurgitation = 4 X (tricuspid
regurgitation velocity)2
 Pulmonary artery systolic pressure is obtained by adding RA pressure to
peak pressure gradient of tricuspid regurgitation, which is calculated by
IVC diameter and inspiratory collapse
 Pulmonary hypertension is defined as mean pulmonary pressure more
than 25mmhg so to convert echo derived systolic pulmonary Pressure in to
mean pressure see below
 “Theoretically calculation of mean pulmonary artery pressure (PAP), from
PA systolic pressure is possible i.e. (mean PAP= 0.61 X PA systolic pressure
+ 2 mmHg)”

36. S.no ECHO parametes notes
1. Record estimated PASP Overestimated -anemia)
Assumes absence of pulmonic stenosis
Echocardiographic PASP does not equal mean PA pressure (definition of PH
guidelines is based on invasive
hemodynamics = mean PA pressure ≥ 25 mm Hg)
2. Evaluate RV size and
function
Signs of RV enlargement (apical 4-chamber view): RV shares apex with LV; RV
bigger than LV; RV basal diameter > 4.2 cm
RV hypertrophy (subcostal view): RV end-diastolic wall thickness > 5 mm ,RV
systolic dysfunction: RV fractional area change < 35%; TAPSE < 1.6 cm; RV
Doppler s′ velocity < 10 cm/s at
base of RV free wall (tricuspid annulus)
Septal flattening in systole => RV pressure overload , in diastole => RV
overload
3. Evaluate for signs of
elevated
PVR
RVOT notching on pulse-wave Doppler profile is sign of elevated PVR ,Peak T
velocity (units = m/s)/RVOT VT I (units = cm) < 0.18: unlikely PVR is elevated
4. Estimate volume status Use size and collapsibility of inferior vena cava (during sniff maneuver) to
determine RA pressure
Hepatic vein flow: systolic flow reversal can be sign of severe T R, RV overload,
and/or increased RV stiffness
Signs of RA overload/enlargement: RA area > 18 cm2; interatrial septum bows
from right to left

37. S.no ECHO parametes notes
5. Evaluate severity of tricuspid
regurgitation
Features suggestive of severe T R include dense T R jet on continuous-wave
Doppler, V-wave cut-off sign; and systolic flow
reversal on hepatic vein pulse-wave Doppler imaging
6. Evaluate for pericardial
effusion
In patients with PAH, the presence of pericardial effusion is poor prognostic
sign
7. Evaluate for causes of PH
(left heart disease, shunt
lesions)
Left heart disease: look for overt LV systolic dysfunction, grade 2 or worse
diastolic dysfunction, severe aortic or mitral
valve disease, and less common abnormalities of left heart (e.g.,
cardiomyopathy, cor triatriatum)
Shunt lesions: perform agitated saline bubble study
8. Differentiate PAH from
pulmonary venous
hypertension
pulmonary venous hypertension: LA enlargement (LA size > RA size);
interatrial septum bows from left to right; E/A ratio > 1.2; E/e′ (lateral) > 11;
lateral e′ < 8 cm/s ,In patients with significantly elevated PASP at rest: grade
diastolic dysfunction pattern (E/A ratio < 0.8) favors PAH
diagnosis because of underfilled LA and decreased LV compliance due to
RV/LV interaction (extrinsic compression of LV by RV.

38. Other modalities
1. V/Q scan
2. Cardiac MRI-
 Excellent assessment of RV function
 RV ED index < 84 ml/m2 ,LVED volume index >40 ml/m2,stroke volume
index > 25ml/m2 : better survival
 RV EF < 35% on CMR poor survival
3. RHC
4.Routine labs for CTDs
5.Functional assessment: minimal difference is by 33 meters.

39. Goals of Treatment
 Current treatment goals include palliating the symptoms
 Improving the exercise tolerance, right ventricular function, and hemodynamics.
 we are still striving to improve survival rates
 clinical trials of PAH are often of insufficient size and duration to demonstrate a
survival.
 Only recent metaanalysis of currently approved therapies has suggested durable effects
on outcomes.

40. Evidence-based treatment algorithm for pulmonary arterial hypertension
patients(2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension)

42. Genereal measures
 Basic counseling and education about the disease
 Low-level graded aerobic exercise such as walking is recommended.
 advised against heavy physical exertion and isometric exercise because this may evoke
exertional syncope.
 Oxygen supplementation to keep the saturation higher than 92% at rest and with exertion,
sleep, or
 A sodium-restricted diet (<2400 mg/day) is advised
 Routine immunizations, such as those against influenza and pneumococcal pneumonia,
 The hemodynamic fluctuations of pregnancy, labor, delivery, and the postpartum period are
potentially life-threatening in patients with PAH, with a maternal mortality rate of 30% to 50%.
 Current guidelines recommend that pregnancy be avoided or be terminated early in women
with PAH(12% mortality)

43. Drugs based on pathways

44. PAH specific therapy
• Nifedipine ,Amlodipine
• Diltiazem
Calcium channel blockers
• Epoprsotenol ,Iloprost
• Treprostinil
• Selexipag
Prostanoids
• Bosentan ,Ambrisentan ,
• Macitentan
Endothelin Receptor
Antagonists
• Sildenafil ,Tadalafil
Phosphodiesterase
Inhibitors
• Riociguat
Soluble Guanylate Cyclase
Stimulators

45. Calcium channel blockers
 effective therapies for the patients with robust response to acute
vasodilator testing: a fall in mPAP of at least 10 mm Hg to an mPAP of 40
mm Hg or less with unchanged or increased CO.
 If patients who meet the definition of an acute response do not improve to
functional class I or II while taking calcium channel–blocking agents, they
should not be considered chronic responders, and an alternative PAH
specific therapy should be prescribed
 Verapamil causes negative inotropy hence should be avoided.

46. Prostanoids
 Prostacyclin, the main product of arachidonic acid in the vascular
endothelium, induces relaxation of vascular smooth muscle by stimulating
the production of cyclic-adenosine monophosphate and inhibits the
growth of smooth-muscle cells.
 In addition, this molecule is the most potent endogenous inhibitor of
platelet aggregation.
 Dysregulation of the prostacyclin metabolic pathways has been shown in
patients with PAH.
 s/E: cough, headache, flushing, diarrhea and jaw pain.

47. Patients, etiology, end points, treatment effects, and adverse reactions in the Pivotal
Phase III Randomized Controlled Trials of the US Food and Drug Administration approved
prostanoids for treatment of pulmonary arterial hypertension in adults.

48. Epoprostenol (Rosanio S, Pelliccia F, et al . Pulmonary Arterial Hypertension in Adults: Novel
Drugs and Catheter Ablation Techniques Show Promise? Systematic Review on Pharmacotherapy and Interventional
Strategies. BioMed Research International. 2014;2014:743868. doi:10.1155/2014/743868.)
 It has a very short half-life (3–6 min) and limited stable time at room temperature
(<8 hours).
 It requires to be continuously administered by an infusion pump or a permanent
indwelling catheter.
 The efficacy of epoprostenol has been tested in three un-blinded randomized
controlled trials in idiopathic/heritable PAH and PAH associated with systemic
sclerosis.
 This agent improves symptoms, exercise capacity, and hemodynamics in both
clinical conditions; however, increased survival rate was only observed in idiopathic
PAH.

49.  The FDA approved epoprostenol in 1995 for PAH patients with WHO
functional classes III and IV who do not respond adequately to
conventional therapy such as diuretics, oral anticoagulants, and long-term
oxygen and digoxin or calcium-channel blockers when indicated.
 It is unusual for a patient to be awaiting lung transplantation without
receiving epoprostenol.
 Subsequent label revisions have included the addition of patients with PAH
related to systemic sclerosis/scleroderma and all patients with PAH
regardless of etiology to improve exercise capacity.
Epoprostenol (Rosanio S, Pelliccia F, et al . Pulmonary Arterial Hypertension in Adults: Novel
Drugs and Catheter Ablation Techniques Show Promise? Systematic Review on Pharmacotherapy and Interventional
Strategies. BioMed Research International. 2014;2014:743868. doi:10.1155/2014/743868.)

50.  Treatment with epoprostenol is initiated at a dose of 2– 4 ng/kg/min, with
doses increasing at a rate limited by side effects (flushing, headache,
diarrhea, and jaw or leg pain).
 The optimal dose varies between individual patients, ranging between 20
and 40 ng/kg/min.
 Serious adverse events related to the delivery system include pump
malfunction, local site infection, catheter obstruction, and sepsis.
 Additionally, abrupt interruption of the infusion should be avoided as, in
some patients, this may lead to a rebound pulmonary hypertension with
symptomatic deterioration and even death.
Epoprostenol (Rosanio S, Pelliccia F, et al . Pulmonary Arterial Hypertension in Adults: Novel
Drugs and Catheter Ablation Techniques Show Promise? Systematic Review on Pharmacotherapy and Interventional
Strategies. BioMed Research International. 2014;2014:743868. doi:10.1155/2014/743868.)

51. Treprostinil
 It has a terminal elimination half-life of ∼2–4 hours
 administered either by inhalation, by a microinfusion pump for continuous subcutaneous
infusion, by a pump for continuous intravenous infusion, or orally.
 Treprostinil was approved by the FDA in 2002 for continuous subcutaneous infusion on
the basis of a 12-week, multicenter, randomized, double-blind, placebo-controlled trial.
 Treprostinil was well tolerated and side effects were typical of prostacyclin treatments.
 In contrast to prior clinical trials, there was no significant treatment effect on the
incidence of clinical worsening. the overall incidence of clinical worsening was quite low.
 Oral treprostinil could provide a convenient, first-line prostacyclin treatment option
for PAH patients not requiring more intensive therapy.

52. Iloprost
 It has a serum half-life from 20 to 25min.
 The pulmonary vasodilating effects of inhaled iloprost last nearly 45 min; therefore,
6 to 9 daily inhalations of 2.5 𝜇g or 5.0𝜇g are needed, with each of them requiring
∼30min.
 Its regulatory FDA approval occurred in 2004 and was based on the results from one
pivotal multicenter trial, AIR (Aerosolized Iloprost Randomized).

53. Selexipag
 an oral, selective prostacyclin receptor agonist that is chemically distinct from
prostacyclin analogs.
 A phase 2 study demonstrated a statistically significant reduction in PVR in patients
with PAH. 47 A placebo-controlled, event-driven, study of selexipag in 1156 patients
with PAH demonstrated a 40% reduction (P < 0.001) in the composite endpoint
of death, hospitalization for PAH, worsening of PAH resulting in the need for
lung transplantation or atrial septostomy, initiation of parenteral prostanoids
or chronic oxygen for worsening of PAH, and disease progression.
 Notably, the effect of selexipag was consistent across subgroups, including
types of treatment (no background therapy vs monotherapy or dual oral
background therapy), disease cause, sex, age, and functional status.
 The most common adverse effects in the selexipag group were consistent with the
known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw
pain.

54. Endothelin-Receptor Antagonists
 The endothelin system has a major role in the pathogenesis of PAH.
 still unknown if the increases in endothelin-1 (ET-1) plasma levels are a cause or a
consequence of PAH.
 The biological effects of ET-1 are regulated primarily by two distinct receptors, ETA and
ETB
 Activation of ETA receptors  vasoconstriction and proliferation of vascular smooth-
muscle cells,
 whereas ETB receptors - pulmonary endothelin clearance and induce the production
of nitric oxide and prostacyclin by endothelial cells that may counterbalance the
deleterious effects of ET-1.
 the efficacy in PAH of dual ETA/ETB receptor antagonist drugs and of selective ETA
blockers appears to be comparable.
 Currently, there are three ET-1 receptor antagonists as first-line use in patients with mild
to moderate PAH: bosentan, ambrisentan, and macitentan.

55. Patients, etiology, end points, treatment effects, and adverse reactions in the Pivotal Phase III
randomized controlled trials of the US Food and Drug Administration approved endothelin-1
receptor antagonists for the treatment of pulmonary arterial hypertension in adults.

56. Bosentan
 an oral active dual ETA/B receptor antagonist
 and its approval in 2001 was based on two randomized, double-blind,
placebo-controlled trials.
 Elevated liver aminotransferase values >3 times normal occurred in
∼13% of patients receiving bosentan, with a higher incidence in the
group receiving the 250mg dose. However, there were no reports of
jaundice or liver failure.
 Despite a greater efficacy with 250 mg dose, the increased risk of
hepatotoxicity resulted in FDA approval of the lower dose of 125mg.
 In addition, FDA approval required patients to obtain liver function tests at
least monthly through a restricted drug distribution program with either
dose reduction, interruption of treatment, or permanent discontinuation
depending upon aminotransferase values.
 Testing for pregnancy is also required monthly in women of childbearing
potential.

57. Ambrisentan
 It is an oral selective ETA-receptor antagonist (ETA versus ETB receptor > 4000-fold)
with a bioavailability and half-life that allow once daily dosing.
 In 2007, the FDA approved 5 and 10mg ambrisentan for the once daily treatment of
patients with PAH and functional class II or III symptoms to improve exercise
capacity and delay clinical worsening.
 Its approval was based on ARIES-1 and ARIES-2 (Ambrisentan in pulmonary arterial
hypertension, RandomIzed, double-blind, placebo-controlled, multicenter, Efficacy
Study) trials.
 Both trials were identical in design (except for overlapping doses) and conducted in
different countries.

58. Ambrisentan
 Improvements in time to clinical worsening (ARIES- 2), WHO functional class (ARIES-
1), several SF-36 Health Survey subscales (quality of life; ARIES-2), Borg dyspnea
score and B-type natriuretic peptide (both studies) were observed.
 In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy,
the improvement from baseline in 6 min walk distance at 48 weeks was 39m.
 Ambrisentan was well tolerated in both trials, with headache being the most
frequent adverse event. No patient treated with ambrisentan developed
aminotransferase concentrations >3 times the upper limit of normal.
 In 2011, the FDA removed the warning label for liver injury and requirement for
monthly liver function testing for ambrisentan on the basis of post marketing data
involving more than 7,800 patient years.

59. Macitentan
 This dual ETA/B receptor antagonist was developed by modifying the structure of
bosentan to increase efficacy and safety.
 Macitentan is characterized by sustained receptor binding and enhanced tissue
penetration.
 In October 2013, the FDA licensed 10mg macitentan for the once daily treatment
of patients with PAH and functional class II or III symptoms to delay disease
progression.
 The approval was based on results from SERAPHIN (Study with an Endothelin
Receptor Antagonist in Pulmonary Arterial Hypertension to Improve cliNical
Outcome), a double-blind, placebo-controlled, Phase III trial.

60. Macitentan
 Women who are prescribed macitentan need to participate in a risk evaluation and
mitigation strategy program due to the risk for fetal harm like other medications
in this class, including bosentan and ambrisentan.
The strengths of SERAPHIN are :
 (1) the largest and longest Phase III outcome trial to date on a novel
pharmacological treatment for PAH; and
 (2) the first study powered for a hard clinical endpoint (morbidity and mortality)
instead of just cha.nge in functional class or 6 min walk distance

61. Phosphodiesterase Type-5 Inhibitors
 The pulmonary vasculature contains sizeable amounts of phosphodiesterase type-5.
 Therefore, a strategy for increasing the activity of endogenous nitric oxide in PAH is to
enhance nitric oxide—dependent, intracellular cyclic guanosine monophosphate (cGMP)—
mediated pulmonary vasodilatation through inhibition of the breakdown of cGMP by
phosphodiesterase type-5. In addition, phosphodiesterase type-5 inhibition has been shown to
exert also antiproliferative effects.
 All three phosphodiesterase type-5 inhibitors approved for the treatment of erectile dysfunction,
sildenafil, tadalafil, and vardenafil cause significant pulmonary vasodilation, with maximum effects
observed after 60, 75-90, and 40–45min, respectively.
 Two randomized controlled trials have tested the effects of orally active phosphodiesterase type-5
inhibitors (namely, sildenafil and tadalafil) in patients with PAH

62. Patients, etiology, end points, treatment effects, and adverse reactions of the US Food and Drug
Administration approved phosphodiesterase type-5 inhibitors in the pivotal Phase III randomized
controlled trials for treatment of pulmonary arterial hypertension in adults.

63. Sildenafil
 It was approved by the FDA in 2005. The approval of sildenafil at 20mg three times
daily for the treatment of patients with PAH was to improve exercise ability,
regardless of the functional class or etiology.

 The approval was based on the results from SUPER-1 (Sildenafil Use in Pulmonary
artERialHypertension-1) trial.
 Of 278 patients treated in SUPER-1, 257 completed the trial and entered an open-
label, uncontrolled extension phase (SUPER-2) receiving the 80mg dose.
 After 3 years, most patients (60%) improved or maintained their functional status
noted at the time of SUPER-1 entry, and 46% maintained or improved their 6 min
walk distance.
 Three-year estimated survival was 79% and no deaths were considered to be
treatment-related.

64. Tadalafil
 In contrast to sildenafil, tadalafil has a long half-life (35 h), which allows once daily
administration.
 It was granted for use by the FDA in 2009. Similar to sildenafil, its regulatory
approval (at a dose of 40mg once daily) was based on the results from a single
pivotal trial, PHIRST (Pulmonary arterial HypertensIon and ReSponse to Tadalafil).
 Data analysis of comparative hemodynamic data from 93 patients, who underwent
repeat right heart catheterization, demonstrated improvements with tadalafil 20 and
40 mg compared to baseline in mean pulmonary arterial pressure and pulmonary
vascular resistance.

65. Guanylate-Cyclase Stimulators
 Soluble guanylate-cyclase is a key enzyme in the nitric oxide signaling pathway.
 On binding of nitric oxide to its prosthetic heme group, soluble guanylate-cyclase
catalyzes the synthesis of the second messenger cGMP, promotes vasodilation and
inhibits smooth muscle proliferation as well as leukocyte recruitment, platelet
aggregation, and vascular remodeling through a number of downstream
mechanisms.
 The central role of the nitric oxide-soluble guanylate-cyclase-cGMP pathway in
regulating pulmonary vascular tone is demonstrated by the dysregulation of nitric
oxide production, soluble guanylatecyclase activity, and cGMP degradation in
PAH

66. Patients, etiology, end points, treatment effects, and adverse reactions of the US Food and Drug
Administration approved soluble guanylate cyclase stimulators in the pivotal Phase III randomized
controlled trials for treatment of pulmonary arterial hypertension in adults.

67. Guanylate-Cyclase Stimulators
 They increase the sensitivity of soluble guanylate-cyclase to endogenous
bioavailable nitric oxide and mimic the effects of nitric oxide when it is absent or
insufficiently produced by endothelial cells.
 The clinical effects of guanylate-cyclase stimulators (namely, Riociguat [licensed in
October 2013 by the FDA]) have been tested in two recently published Phase III
randomized controlled trials, PATENT-1 and CHEST-1.
 Of note, in open-label extension studies (PATENT-2 and CHEST-2), Riociguat
patients exhibited further increases in 6 min walk distance by 10–20m over 12
weeks of additional treatment; these were then maintained for an entire year
of therapy.

69. Combination of FDA Approved Drugs therapy

81. Palliation
Atrial septostomy
 Severe PAH and failure of medical therapy
 A bridge
 Lung transplant