1. General Overview of Pulmonary Hypertension
Tasbirul Islam MD,FCCP,MRCP(UK)
Indiana University Hospital Arnett
Lafayette , IN

2. General Overview of Pulmonary Hypertension
Discuss the different etiologies of pulmonary hypertension with focus on pulmonary arterial hypertension.
Discuss diagnostic and treatment approach to pulmonary arterial hypertension.
Give overview on all pharmacologic and non-pharmacologic treatment options for pulmonary arterial hypertension.

3. What is the most common cause of pulmonary hypertension?
Left heart failure
Connective tissue disorder
Idiopathic
Pulmonary embolism

4. An echocardiogram is not adequate to diagnose pulmonary arterial hypertension.
True
False

5. Calcium channel blockers are considered first line therapy for pulmonary arterial hypertension.
True
False

6. Prostacyclins are the last option that should be used to treat pulmonary arterial hypertension.
True
False

7. Oral or inhaled medication shouldn’t be used in class IV
Yes No

8. Anticoagulation should be used only in IPAH
True
False

9. Pulmonary Hypertension
Concept…
…progressive increase in the blood pressure in the pulmonary vascular bed
Consequence…
…right heart failure and death

11. PAH is a rare disease Incidence of IPAH: ~1-2 cases/million per year
Prevalence: 5,000 patients?
Prevalence of PAH: 30,000 patients?
~50 million Americans have systemic hypertension
61% of American adults are overweight
27% are obese (BMI>30)
16% of Americans have diabetes
22% have hyperlipidemia

12. Definitions of Pulmonary Hypertension
Pulmonary arterial hypertension (PAH)
Precapillary
Very rare
Prevalence < 30/million
Pulmonary venous hypertension
Postcapillary
Common

13. Hemodynamic Definition of PH/PAH
Mean PAP ≥25 mm Hg
Mean PAP ≥25 mm Hg plus PCWP/LVEDP ≤15 mm Hg
PAH
The hemodynamic working definition of PAH listed here is derived from the 2009 Proceedings of the 4th World Symposium on PH. In the new recommendations, exercise and PVR criteria have been eliminated.
An accurate PCWP can be difficult to obtain in patients with PH and enlarged pulmonary arteries.
If PCWP is elevated despite multiple attempts, especially if blood obtained in the wedge position is not fully saturated, direct measurement of LVEDP should strongly be considered so as not to misdiagnose patients who have PAH.
In a recent retrospective study of 4300 patients undergoing simultaneous right and left catheterization, 53% meeting criteria for PAH on the basis of a PCWP <15 had a LVEDP >15 (even among patients being evaluated specifically for PH)
Refs: Badesch et al. JACC 2009;126:in press. Halpern SD, Taichman DB. Chest, Mar 24. [Epub ahead of print].
ACCF/AHA CECD includes PVR >3 Wood Units
Badesch D et al. J Am Coll Cardiol. 2009;54:S55-S66.
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

14. Why does the Right Heart Fail?
Right Circulation
Low pressure system
20/10
Right ventricle has thin muscle wall
Not adaptable to higher strain
Left Circulation
High pressure system
120/80
Left ventricle has thick muscle wall
More adaptable to higher strain

15. Clinical Classification of Pulmonary Hypertension (Dana Point)
1. PAH
Idiopathic PAH
Heritable
Drug- and toxin-induced
Persistent PH of newborn
Associated with:
CTD
HIV infection
portal hypertension
CHD
schistosomiasis
chronic hemolytic anemia
1’. PVOD and/or PCH
2. PH Owing to Left Heart Disease
Systolic dysfunction
Diastolic dysfunction
Valvular disease
3. PH Owing to Lung Diseases and/or Hypoxia
COPD
ILD
Other pulmonary diseases with mixed restrictive and obstructive pattern
Sleep-disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental abnormalities
4. CTEPH
5. PH With Unclear Multifactorial Mechanisms
Hematologic disorders
Systemic disorders
Metabolic disorders
Others
The clinical classification of pulmonary hypertension, updated at the 4th World symposium, is represented here.
PAH is represented in the first subgroup. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis are housed within this classification, but in a separate group, distinct from but very close to Group 1 (now called Group 1-prime).
Of note, left heart disease (Category 2) probably represents the most frequent cause of PH. Therefore, it is critically important in the diagnostic work-up to distinguish right heart form left heart disease.
The predominant cause of PH in Category 3 is alveolar hypoxia as a result of lung disease, impaired control of breathing, or residence at high altitude.
Patients with suspected or confirmed CTEPH (Category 4) should be referred to a center with expertise in the management of this disease.
Group 5 comprises several forms of PH for which the etiology is unclear or multifactorial.
Simmoneau G et al. J Am Coll Cardiol. 2009;54:S43-S54.
Simonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.

16. REVEAL Study 54 center study to characterize PAH in US
2,967 adult/pediatric WHO Group I PAH pts from 3/06 to 9/07
Mean time from symptoms to dx RHC 34.1 mo (2.8 yrs)
All Patients
APAH Patients
Badesch, Chest 2010; 137:376

17. REVEAL Study IPAH APAH CVD/CTD Number 1,166 1,280 639 Age Dx 49.9 50.7
55.5
Female
80.3%
79.2%
90.1
mPAP
52.1
49.1
44.9
PVRI
22.9
19.0
16.9
Cardiac Index
2.2
2.5
Badesch, Chest 2010; 137:376

18. Pathogenesis of PAH 1 2 Vascular Injury 3 Disease Progression
Endothelial Dysfunction
↓ Nitric Oxide Synthase
↓ Prostacyclin Production
↑ Thromboxane Production
↑ Endothelin 1 Production
Vascular Smooth Muscle Dysfunction
Impaired Voltage-Gated Potassium Channel (KV1.5) 3
Disease Progression
Loss of Response to
Short-Acting
Vasodilator Trial
Risk Factors and Associated Conditions
Collagen Vascular Disease
Congenital Heart Disease
Portal Hypertension
HIV Infection
Drugs and Toxins
Pregnancy
Susceptibility
Abnormal BMPR2 Gene
Other Genetic Factors
Smooth muscle hypertrophy
Adventitial and intimal proliferation
In situ thrombosis
Adventitia
Smooth muscle hypertrophy
Media
Plexiform lesion
Early intimal proliferation
Intima
Normal
Reversible Disease
Irreversible Disease
Gaine S. JAMA. 2000;284:

19. Isolation of an IPAH Gene
Bone Morphogenetic Protein Receptor II (BMPR2)
Member of TGF-b receptor superfamily
11-40% Idiopathic and 70% Familial PAH
Autosomal dominant
Penetrance estimated at 20%
Genetic anticipation
Deng et al, Am J Hum Genet 2000; 67:737 Lane et al, Nat Genet 2000; 26: Thomson et al, J Med Genet 2000; 37:741

20. Clinical Manifestations & Diagnostic Workup

21. Clinical Presentation
Nonspecific symptoms
Dyspnea initial sx in 60%, at dx 98%
Fatigue 73%
Chest pain 47%
Edema 37%
Syncope 36%
Palpitations 33%
Mean time from onset sx to diagnosis 2 yrs
Rich, Ann Intern Med 1987; 107:216

22. Recommendations Diagnostic Strategy
Class
Level
Ventilation/perfusion lung scan is recommended in patients with
unexplained PH to exclude CTEPH.
Contrast CT angiography of the PA is indicated in the work-up of patients
with CTEPH
Routine biochemistry, haematology, immunology and thyroid function
tests are indicated in all patients with PAH, to identify the specific
associated condition.
Abdominal ultrasound is indicated for the screening of portal hypertension.
High-resolution CT should be considered in all patients with PH
Conventional pulmonary angiography should be considered in the work-up
of patients with CTEPH.
Open or thoracoscopic lung biopsy is not recommended in patients with PAH. I
IIa C
III
European Heart Journal 2009;30:

23. Radiography
November 2005
September 1997

24. Radiography
November 2005
September 1997

25. Enlarged main PA on CT Standard view Coronal view

26. Electrocardiogram

27. Echocardiography
Pulmonary HTN
Normal

28. CTEPH, 0.6% Lung disease/ PAH, 2.3% Sleep-related hypoventilation,
Left heart
disease, 78.7%
PAH, 2.3%
Congenital heart
disease, 1.9%
Lung disease/
Sleep-related
hypoventilation,
9.7%
CTEPH, 0.6%
Unknown, 6.8%
It is important to recognize that while echo is an excellent screening tool when there is suspicion of PH, the echo and cath are complementary, and one cannot substitute for the other.
This slide depicts data from a single echo lab on the ultimate diagnosis reached in 483 patients found to have PH on echo.
Not unexpectedly, the majority had left heart disease and, importantly, only a small number (2%) had PAH.
While these data are subject to referral bias and we cannot be certain of the diagnostic criteria used, the point remains:
The echo and cath are each essential.
We cannot be certain of PAH on the basis of the echo alone.

29. Echo estimate of PAP often inaccurate in advanced lung disease
Overestimation
Accurate
Underestimation
Cohort: 374 lung txp pts
Echo 24–48 h prior to RHC
Prevalence of PH: 25%
Echo frequently leads to over-diagnosis of PH in patients with advanced lung disease 20 40 60
% of studies
Although the echo is often remarkably accurate in its estimate of pulmonary pressures, in certain situations (as depicted here in patients with advanced lung disease undergoing evaluation for transplant) it can be less reliable.
The point is NOT that echo is less valuable.
Echo provides important structural, valvular, functional data that are complementary to the cath.
Rather, the point is that both tests are essential to be certain of the right diagnosis.
PH (-)
PH (+)
Arcasoy SM et al. Am J Respir Crit Care Med. 2003;167:

30. European Heart Journal 2009;30:2493-2537
Arbitrary criteria for detecting the presence of PH based on tricuspid regurgitation peak velocity and Doppler-calculated PA systolic pressure at rest*
Echocardiographic diagnosis: PH unlikely
Tricuspid regurgitation velocity ≤ 2.8 m/sec, PA systolic pressure ≤ 36 mmHg
and no additional echocardiographic variables suggestive of PH
Echocardiograohic Diagnosis PH possible
but presence of additional echocardiographic variables suggestive of PH.
Tricuspid regurgitation velocity m/sec, PA systolic pressure mmHg
with or without additional echocardiographic variables suggestive of PH
Echocardiographic diagnosis: PH likely
Tricuspid regurgitation velocity > 3.4 m/sec, PA systolic pressure > 50 mmHg
with/without additional echocardiographic variables suggestive of PH
Exercise Doppler echocardiograpy is not recommended for
screening of PH.
European Heart Journal 2009;30:

31. Pulmonary Function Testing
Spirometry
Lung Volumes
Diffusion Capacity
Mildly-moderately reduced (69% NIH study)
Severely reduced think CVD
Arterial Blood Gas
Significant hypoxemia not common in IPAH unless PFO present
Often normal or mild restriction
Rich, Ann Intern Med 1987; 107:216

32. Ventilation-Perfusion Lung Scan

33. Evaluation for Chronic Thromboembolic PH (CTEPH)
V/Q scan remains the best screening tool
CT angiogram is excellent for acute, proximal PE but can miss CTEPH
Gold standard for diagnosis is pulmonary angiogram
Safe procedure even in patients with marked PH
Mortality in 2 large studies: 0/547 and 2/202* PE
No PE
Tanariu, N. et al,
J Nucl Med, 2007
*Hofman LV, et al, AJR, 2004
Pitton MB, et al, AJR, 2007

34. Laboratory Routine labs ANA positive in 29% CBC with differential
Autoantibodies – ANA, RF, α-dsDNA Ab, ENA’s
HIV Ab
Liver function tests
Thyroid studies
ANA positive in 29%
Rich, Ann Intern Med 1987; 107:216

35. Importance of Right Heart Cath
PAWP
LVEDP
LAP PH
PVR
TPG
PVH
PAH
PAH (Group 1)
Hypoxic/Lung
CTEPH
LH Disease
PV Obstruction
CO
Right heart catheterization (RHC) is the diagnostic gold standard for PH.
RHC is required to confirm the diagnosis of PH and assess its severity (for prognosis), exclude left heart disease, and perform vasoreactivity testing.
This Venn diagram shows hemodynamic classes of PH, their relative frequency, and the characteristics of each.
Among patients with PH, the majority have pulmonary venous hypertension (“passive” or “post-capillary” PH) related to diseases of the left heart.
These patients will have elevated PAWP, LVEDP and/or LAP related to left heart disease (typically with normal PVR).
Patients with PAH have increased PVR and TPG (with normal left-sided filling pressures).
These hemodynamic findings are also seen in patients with hypoxia, parenchymal lung disease, and CTEPH.
Patients with a high CO state (“hyperkinetic” PH), such as with fever, thyrotoxicosis, anemia, pregnancy, and some cases of portopulmonary hypertension, have elevated CO yet normal LV filling pressure and PVR.
PBF
Fever
Thyrotoxicosis
Anemia
Pregnancy
Some PoPH

36. Right Heart Catheterization
Right atrial pressure
Pulmonary arterial pressure
Pulmonary vascular resistance
Pulmonary arterial occlusion pressure
Cardiac output
Shunt run
+/- Left heart cath data
Left ventricular end diastolic pressure
Coronary angiography
Diagnostic Criteria mPAP > 25 mm Hg rest PAOP/LVEDP < 15 mm Hg

37. Treatment of PAH
Humbert, NEJM 2004; 351:1425

38. General Therapies Anticoagulants – only studied in IPAH Diuretics
Digoxin
Oxygen
Salt restriction
Rehab

39. Early Intervention, Regular Monitoring, and Escalation of Treatment
No functional impairment
Functional Capacity
ERS Showreel 2009
Progressive remodeling and right heart failure
in absence of treatment
Late intervention
Time

40. Early Intervention, Regular Monitoring, and Escalation of Treatment (cont)
No functional impairment
Will escalation of therapy and achievement of goals improve long-term outcomes?
Functional Capacity
ERS Showreel 2009
Early intervention
Progressive remodeling and right heart failure
in absence of treatment
Late intervention
Time

41. Prostacyclin Analogues: Oral, Intravenous, Subcutaneous, or Inhaled
Epoprostenol (Flolan®)
Treprostinil (Remodulin®)
Treprostinil (Remodulin®)
Iloprost (Ventavis®)
Treprostinil (Tyvaso®)
Prostacyclin and prostacyclin analogues are available in intravenous (IV), subcutaneous (SC), and inhaled formulations.
These drug delivery systems are complex.
IV epoprostenol and treprostinil require a chronic indwelling central venous catheter, usually a tunneled catheter exiting the left upper or right upper chest wall.
Potential complications: infection (blood stream, tunnel, or exit site infection), thrombosis, accidental removal, device malfunction.
SQ trepostinil
Treprostinil, a prostacyclin analogue, has a longer half-life (approximately 4.5 hr) than epo (≤6 min), and can be administered SC.
Potential complications: 85% of patients reported incidence of infusion pain and/or site reaction (redness and swelling, not dose related), leading to discontinuation in 8%. Significant infection is rare.
Iloprost is administered via iNeb device (hand-held portable device).
Takes approx 6-10 min to deliver the total dose, depending on the patient’s breathing pattern, plus up to 10 min per session for device cleaning (time reduced recently with new cleaning system)
Since the dose frequency is 6-9 times per day (every 2 hours while awake), it can be cumbersome. A new inhaled form of treprostinil has just been approved.
Uses a battery-operated, rechargeable ultrasonic nebulizer
Uses single-breath technology (dosing 3-9 breaths), allowing each treatment to be completed in <1 min
Dosing is 4 times per day (every 4 hours awake)

42. Epoprostenol (PGI2) First agent FDA approved for PAH
Half-life 3-5 minutes
Hydrolysis in plasma
Single-lumen catheter for continuous intravenous administration
Unstable at room temperature
CADD-1 Pump

43. VELETRI
Once-weekly preparation (up to 8 cassettes at one time), and which, when prepared, stored, and used as directed,
Does not require ice packs.
Don't need special mixing liquids (diluents) to prepare medicine.
24-hour room temperature stability at all concentrations.

44. Prognosis with Epoprostenol
French cohort of 178 IPAH vs historical controls
Survival rates of
85% 1 year
70% 2 years
63% 3 years
55% 5 years
76 episodes of catheter-related infxn’s (0.19 per patient yr), 4 deaths
Sitbon, JACC 2002; 40:780

45. Epoprostenol (Flolan)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

46. Treprostinil Prostacyclin analogue Half-life 4 hours
IV or SQ continuous infusion
Inhaled delivery
No need for refrigeration
33-50% less potent than epoprostenol
Site pain problematic with SQ route- 2/3 pts
Mini-Med 407C Pump

47. Treprostinil (Remodulin)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

48. Treprostinil (Remodulin)
Intravenous treprostinil
Hemodynamic improvements and 6MWD improvements 1
No site pain
Risk of catheter related bloodstream infection and embolic phenomenon
Recent concerns about increased gram-negative bloodstream infections (CDC MMWR March 2, 2007 / 56(08); )
1Tapson VF et al. Chest 2006;129:683-88

49. Iloprost Inhaled prostacyclin analogue 5 mcg dose 6x per day
5-10 minutes for inhalation
Half-life minutes
I-Neb

50. Inhaled Treprostinil (Tyvaso)
Inhaled prostacyclin
Administered 4 times daily
Proprietary nebulizer
TRIUMPH study showed improvements in 6MWD

51. Oral Prostanoid analog
Beraprost sodium—Only available in Japan
--Alphabet trial in Europe showed excessive AE’s thought 6 MWT showed slight improvement
--North Americal Beraprost trial--North American PAH trial was terminated due to concerns for lack of efficacy.
Oral Treprostinil ()—FDA approved in Dec’2013,
--FREEDOM trial showed patients receiving treprostinil twice daily improved their median six-minute walk distance (6MWD) by +23 meters.

52. Oral prostacycline receptor agonist
---Selexipag (Uptravi)—FDA approved in Dec’15
---GRIPHON study showed decrease risk of a morbidity/mortality events compare with placebo.

53. Prostanoid Side Effects
Hypotension
Dizziness
Syncope
Cough (inhaled)
Delivery site complications
Flushing
Headache
Diarrhea, nausea, vomiting
Jaw pain
Leg pain
The side effects of prostanoids (including epoprostenol, treprostinil, and iloprost) are essentially the same, but they vary according to the drug, dose escalation, and route of delivery.
Cough is unique to iloprost and related to its inhalational route of delivery.
Delivery site complications for IV epo and treprostinil can lead to CRBSI/sepsis, tunnel and exit site infections, thrombosis.
SQ trepostinil causes infusion site pain and reaction (redness and swelling, which is not dose-related) in 85% of patients (leading to drug discontinuation 8%), but it is rarely associated with a serious infection
Vary according to drug and route of delivery

54. Endothelin-1 Receptor Antagonists
Bosentan
62.5 mg bid x 4 weeks then 125 mg bid
10% LFT abnormalities (monitor monthly)
Pregnancy category X
Ambrisentan
mg daily
No reported LFT abnormalities
Edema main side effect

55. Bosentan (Tracleer) • 215 patients 70% IPAH 92% Class III • Week 16:
36 meter
Improvement
44 meter treatment
effect
1Adapted from Rubin LJ et al. N Engl J Med 2002;346:

56. Bosentan (Tracleer) Improved Hemodynamics
mRAP
Δ mm Hg
(p=0.001) CI
Δ L/min/m2
(p=0.001 )
PVR
Δ - 415dyn/sec/cm-5
(p=0.001)
PAP
Δ mm Hg
(p<0.02)
+4.9 ± 4.6
50%
40%
Change from baseline (%)
30%
+0.5 ± 0.5
+191 ± 235
20%
+5.1 ± 8.8
10%
Hemodynamic measurements were taken at baseline and 12 weeks in Study 351.
All hemodynamic parameters improved in the Tracleer group while all parameters deteriorated in the placebo group.
This slide displays the data in 2 methods:
1) The y-axis represents the % change from baseline in the 4 hemodynamic parameters.
2) The slide also displays the absolute change from baseline as well as the overall treatment effect for each hemodynamic parameter, for both placebo and bosentan.
There was a mean improvement of 0.5 L/min/m2 in the CI for the Tracleer group, compared with a 0.52 L/min/m2 decrease in the placebo group. The overall treatment effect was +1.0 L/min/m2 (p ≤ 0.001).
There was a mean reduction in mRAP of 1.3 mm Hg in the Tracleer group, compared with a 4.9 mm Hg increase in the placebo group. The overall treatment effect was 6.2 mm Hg (p ≤ 0.001).
There was a mean reduction in PVR of 223 dyn-sec-cm-5 in the Tracleer group, compared with a 191 dyn-sec cm-5 increase in the placebo group. The overall treatment effect was 415 dyn-sec-cm-5 (p≤0.001).
There was a mean decrease of 1.6 mm Hg in PAP in the Tracleer group, compared with a 5.1 mm Hg increase in the placebo group. The changes versus baseline did not reach significance, but the treatment effect did (6.7 mm Hg; p<0.02).
(There was only a 0.1 mm Hg increase in PCWP in the Tracleer group, compared with a 3.9 mm Hg increase in the placebo group. The overall treatment effect was 3.8 mm Hg (p=0.035).)
Reference:
Adapted from Channick R, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358: 0%
-1.6 ± 5.1
-10%
-1.3 ± 4.1
-20%
-0.5 ±0.5
-223 ± 245
-30%
Placebo
Tracleer
One patient in each treatment group had no valid week 12 assessment and was not included in the analysis.
Adapted from Channick, et al. Lancet 2001

57. Phosphodiesterase 5 Inhibitors
Prevent breakdown of cGMP the downstream mediator of nitric oxide
Sildenafil 20 mg tid
Tadalafil 40 mg daily
Major side effects
Vasodilatory- headaches, flushing, sinus congestion
Visual color changes and blurriness

58. Sildenafil (Revatio)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06

59. Effect of Tadalafil* on 6MWD (PHIRST)70 60 50 40 30 20 10
Placebo
Tadalafil 2.5 mg
Tadalafil 10 mg
Tadalafil 20 mg
Tadalafil 40 mg
p<0.001
p<0.05
Change in 6MWD (m)
p<0.05
Tadalafil is the newest PDE-5 inhibitor available for the treatment of PAH.
PHIRST was a 16-week, double-blind, placebo-controlled study of 405 patients with PAH (idiopathic or associated), either treatment-naive or on background therapy with the bosentan, randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily.
Tadalafil produced increases 6MWD in a dose-dependent manner, with the 40-mg dose meeting the prespecified level of statistical significance (p<0.01).
The mean placebo-corrected treatment effect was 33 m (95% Cl, 15 to 50 m). Among bosentan-naïve patients, the treatment effect was 44 m (95% CI, 20 to 69 m) compared with 23 m (95% confidence interval, -2 to 48 m) among patients on background bosentan therapy.
Galiè N et al. Circulation. 2009;119: 4 8 12 16
Weeks
*Adcirca®
Galiè N et al. Circulation. 2009;119;

60. Calcium Channel Blockers
Retrospective study of all 557 IPAH pts at single institution from 6/84-9/01
Responders defined by > 20% drop in mPAP & PVR to intravenous epoprostenol or inhaled NO
Nifedipine 10 mg tid or Diltiazem 60 mg tid and uptitrated
Long-term responders defined by NYHA I-II with sustained hemodynamic improvement at 1 yr
70 pts (12.6%) displayed acute reactivity with 38 long-term responders (6.8%)
Long-term responders more vasoreactive, less severe dz, and longer duration of symptoms
Hemodynamic improvements maintained at mean f/u of 5.3 yrs
Sitbon, Circulation 2005; 111:3105

61. Kaplan-Meier Mortality Estimates Acute Vasodilator Testing
Only 1 Long-term responder died (breast CA with stable PAH)
Current Consensus Guidelines on Acute Vasoreactivity Response
Decrease in mPAP by > 10 mm Hg
Decrease in absolute mPAP below 40 mm Hg
Unchanged or improved Cardiac Output
Sitbon, Circulation 2005; 111:3105

62. Calcium Channel Blockers Only If “Vasodilator Responsive”
“Vasodilator Response”
Fall in mPAP ≥10 mm Hg
PLUS
mPAP (absolute) <40 mm Hg
Normal or Increase CO
Thus, CCBs must NOT be used without initially demonstrating that pts have a true acute vasoreactivity to a short-acting vasodilator in the cath lab (adenosine, NO, IV epo)
And the response is not a subtle one. Pts with a reasonable chance of having a clinical response to CCBs go a long way toward normalizing their hemodynamics with acute testing– it is not just a small decrement in mPA pressure or 5% drop in PVR.
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

63. Comparisons of Therapies
Cost $
(annual)
Route
Frequency
Long-term
Data
Epoprostenol
~100K IV
Continuous
Yes
Bosentan
~65K
Oral
BID
Ambrisentan QD
Treprostinil
>100K
SQ, IV
Iloprost
125K
Inhaled
5-7X per day No
150K
QID
Tadalafil
~ 15K
Sildenafil
~15-20K
TID

64. Country-specific regulatory approval d labeling for PAH-specific drug therapy
Treatment
Country
Labelling
Aetiology WHO-FC
Calcium channel blockers -
Ambrisentan
USA, Canada
European Union
PAH
II – III – IV
II – III
Bosentan
Sitaxentan
III
Sildenafil
Tadalafil
USA
II – III - IV
Treatment
Country
Labelling
Aetiology WHO-FC
Iloprost
(inhaled)
European Union
USA
IPAH
III
III - IV
(intravenous)
New Zealand
PAH-CTD
and CTEPH
III – IV
Treprostinil
(subcutanaeous)
Canada
PAH
II – III - IV
II – III – IV
III-IV
European Heart Journal 2009;30:

65. PAH (Group 1) Medication Options
Mild Moderate Severe
25 <MPAP< <MPAP< MPAP> 50
Ca++ Channel Blocker X
Endothelin antagonist X X
PDE-5 inhibitor X X
Prostanoids X X
Inhaled iloprost X X
SQ treprostinil X X
IV epoprostenol X X
Oral Prostaoids X X

66. Riociguat (a stimulator of soluble guanylate cyclase) significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension.
N Engl J Med 2013;369:

67. …other therapeutic options
If chronic pulmonary emboli…
pulmonary thromboendarterectomy surgery
If all meds fail…
atrial septostomy
organ transplantation
heart-double lung
double lung

68. Pulmonary Rehabilitation:
30 stable, medically optimized PAH pts, 80% NYHA III-IV
Randomized to 15 wk rehab program with 1st 3 wks inpatient
Control – standard rehab w/ nutrition, PT, counseling
Rehab – exercise training w/ bike and walking
3 wk – Δ6MW was 12 m control, 85 m rehab
15 wk – Δ6MW was -15 m control, 96 m rehab
7 pts in rehab group improved NYHA FC, none in control group
Mereles, Circulation 2006; 114:1482

69. LUNG TRANSPLANTATION The only cure for PAH
IPAH in UNOS database
Survival was calculated using the Kaplan-Meier method, which incorporates information from all transplants for whom any follow-up has been provided. Since many patients are still alive and some patients have been lost to follow-up, the survival rates are estimates rather than exact rates because the time of death is not know for all patients. Survival rates were compared using the log-rank test statistic.
P = 0.3

70. Prognosis Modern French Registry
190 pts with PAH from idiopathic, familial, or anorexigens
Dx during or w/in 36 months of 10/02 to 10/03
81% idiopathic
68% NYHA III
All pts received therapy
Survival Estimates
1yr – 83%, 2 yr – 67%, 3 yr – 58%
Humbert, Circulation 2010; 122:156

71. Survival of Patients With Idiopathic PAH According to NYHA FC at Diagnosis
100 80
NYHA FC I/II 60
NYHA FC III
% survival 40
NYHA FC IV 20
N = 190 12 24 36
Time (months)
FC = functional class
Humbert M, et al. Circulation. 2010;122:

72. Survival in PAH
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Congenital heart disease
Portopulmonary
Percent survival
IPAH
CTD
In the absence of effective therapy, prognosis of idiopathic PAH (idiopathic PAH [iPAH], and other forms of PAH) is very poor.
Median survival 2.8 yrs from diagnosis
Over 50% of untreated patients will die within 5 yrs.
Prognosis over the first 3 years is particularly poor in patients with PH secondary to connective tissue disease (CTD) and human immunodeficiency virus (HIV).
Over the past 10 years, 7 approved therapies for PAH have become available, and additional agents and classes of drugs are currently being evaluated.
This slide emphasizes how deadly a disease PAH can be, and why it is imperative that clinicians actively screen for it so as to improve outcomes.
HIV 1 2 3 4 5
Years
McLaughlin VV et al. Chest. 2004;126:78S-92S.

73. Longitudinal Evaluation of the Patient
Stable; no increase in symptoms and/or decompensation
Clinical course
Unstable; increase in symptoms and/or decompensation
No evidence of right heart failure
Physical exam
Signs of right heart failure
I/II
WHO functional class IV
> 400 m
6MW distance
< 300 m
RV size/function normal
Echocardiography
RV enlargement/dysfunction
RAP normal; CI normal
Hemodynamics
RAP high; CI low
Near normal, remaining stable, or decreasing
BNP
Elevated or increasing
Oral therapy
Treatment
IV prostacyclin and/or combination treatment
McLaughlin V et al. J Am Coll Cardiol. 2009;53:

74. Longitudinal Evaluation (cont)
Stable; no increase in symptoms and/or decompensation
Clinical course
Unstable; increase in symptoms and/or decompensation
Every 3-6 months
Frequency of evaluation
Every 1-3 months
Every clinic visit
Functional class assessment
6MW distance
Every 12 months or center dependent
Echocardiography
Every 6-12 months or center dependent
Center dependent
BNP
Clinical deterioration and center dependent
Right heart catheterization
Every 6-12 months or clinical deterioration
McLaughlin V, et al. J Am Coll Cardiol. 2009;53:

75. What Is the Optimal Treatment Strategy?
Anticoagulate ± Diuretics ± Oxygen ± Digoxin
Acute Vasoreactivity Testing
Positive
Oral CCB
Negative No
Lower Risk
Determinants of Risk
Higher Risk No
Clinical evidence of RV failure
Yes
Gradual
Progression of symptoms
Rapid
II, III
WHO class IV
Longer (> 400 m)
6MWD
Shorter (< 300 m)
Peak VO2 > 10.4 mL/kg/min
CPET
Peak VO2 < 10.4 mL/kg/min
Minimal RV dysfunction
Echocardiography
Pericardial effusion, significant RV enlargement/ dysfunction; RA enlargement
RAP < 10 mm Hg; CI > 2.5 L/min/m2
Hemodynamics
RAP > 20 mm Hg; CI < 2.0 L/min/m2
Minimally elevated
BNP
Significantly elevated
Sustained Response
Continue CCB
Yes
McLaughlin V, et al. J Am Coll Cardiol. 2009;53:
What is the optimal treatment strategy?
For patients with a negative acute vasodilatory test, it is helpful to start with an assessment of our patients’ risk profiles.
Forms-PHD/Powerpoint-PH/ACC 2002-VM.ppt 75

76. Take Home Points
PH can not be diagnosed by Echo alone, need a thorough evaluation for all patients
Right heart catheterization is necessary in ALL patients to accurately diagnose PH
PAH is a progressive disease, even with Rx
Make sure the patient has PAH before treating
Despite multiple therapies, lung transplantation is the only curative treatment for PAH

77. What is the most common cause of pulmonary hypertension?
Left heart failure
Connective tissue disorder
Idiopathic
Pulmonary embolism

78. An echocardiogram is not adequate to diagnose pulmonary arterial hypertension.
True
False

79. Calcium channel blockers are considered first line therapy for pulmonary arterial hypertension.
True
False

80. Prostacyclins are the last option that should be used to treat pulmonary arterial hypertension.
True
False

81. Oral or inhaled medication shouldn’t be used in class IV
True
False

82. Anticoagulation should be used only in IPAH
True
False