Download Pulmonary Hypertension

Tasbirul Islam MD,FCCP,MRCP(UK)
Indiana University Hospital Arnett
Lafayette , IN
General Overview of
Pulmonary Hypertension
1.
2.
3.
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 nonpharmacologic treatment options for pulmonary arterial
hypertension.
What is the most common cause of pulmonary
hypertension?
1.
2.
3.
4.
Left heart failure
Connective tissue disorder
Idiopathic
Pulmonary embolism
An echocardiogram is not adequate to diagnose
pulmonary arterial hypertension.
1.
2.
True
False
Calcium channel blockers are considered first line
therapy for pulmonary arterial hypertension.
1.
2.
True
False
Prostacyclins are the last option that should be used to
treat pulmonary arterial hypertension.
1.
2.
True
False
Oral or inhaled medication shouldn’t be used in class IV
1. Yes
2. No
Anticoagulation should be used only in IPAH
1. True
2. False
Pulmonary Hypertension
Concept…
…progressive increase in the blood pressure in the
pulmonary vascular bed
Consequence…
…right heart failure and death
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
Definitions of Pulmonary Hypertension
 Pulmonary arterial
hypertension (PAH)
 Precapillary
 Very rare
 Prevalence < 30/million
 Pulmonary venous
hypertension
 Postcapillary
 Common
Hemodynamic Definition of PH/PAH
PH
PAH
Mean PAP ≥25 mm Hg
Mean PAP ≥25 mm Hg plus
PCWP/LVEDP ≤15 mm Hg
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;53:1573-1619.
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
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
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
1’. PVOD and/or PCH
5. PH With Unclear Multifactorial Mechanisms
2. PH Owing to Left Heart Disease
• Systolic dysfunction
• Diastolic dysfunction
• Valvular disease
Simonneau G et al. J Am Coll Cardiol. 2009;54;S43-S54.
• Hematologic disorders
• Systemic disorders
• Metabolic disorders
• Others
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
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
2.5
Badesch, Chest 2010; 137:376
Pathogenesis of PAH
1 Risk Factors and
Associated Conditions
2
Collagen Vascular Disease
Congenital Heart Disease
Portal Hypertension
Susceptibility
HIV Infection
Abnormal BMPR2
Drugs and Toxins
Gene
Pregnancy
Other Genetic
Factors
Adventitia
Media
Intima
Normal
Vascular Injury
3 Disease Progression
Endothelial Dysfunction
Loss of Response to
↓ Nitric Oxide Synthase
Short-Acting
↓ Prostacyclin Production
Vasodilator Trial
↑ Thromboxane Production
↑ Endothelin 1 Production
Smooth muscle
Vascular Smooth Muscle
hypertrophy
Dysfunction
Impaired Voltage-Gated
Potassium Channel (KV1.5) Adventitial and
Smooth muscle
hypertrophy
Early intimal
proliferation
intimal proliferation
In situ
thrombosis
Plexiform
lesion
Reversible Disease
Gaine S. JAMA. 2000;284:3160-3168.
Irreversible Disease
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
Recommendations Diagnostic
Strategy
Class Level
• Ventilation/perfusion lung scan is recommended in patients with
I
C
I
C
I
C
• Abdominal ultrasound is indicated for the screening of portal hypertension.
IIa
C
• High-resolution CT should be considered in all patients with PH
IIa
C
IIa
C
III
C
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.
• 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.
European Heart Journal 2009;30:2493-2537
Radiography
November 2005
September 1997
Radiography
November 2005
September 1997
Enlarged main PA on CT
Standard view
A
PA
Coronal view
Electrocardiogram
Echocardiography
Pulmonary HTN
Normal
Lung disease/ CTEPH, 0.6%
Sleep-related
hypoventilation,
9.7%
PAH, 2.3%
Unknown, 6.8%
Congenital heart
disease, 1.9%
Left heart
disease, 78.7%
Echo estimate of PAP often inaccurate in
advanced lung disease
 Cohort: 374 lung txp pts
Overestimation
Accurate
Underestimation
60
 Echo 24–48 h prior to RHC
 Prevalence of PH: 25%
diagnosis of PH in patients
with advanced lung disease
% of studies
 Echo frequently leads to over-
40
20
0
Arcasoy SM et al. Am J Respir Crit Care Med. 2003;167:735-740.
PH (-)
PH (+)
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
•Tricuspid regurgitation velocity ≤ 2.8 m/sec, PA systolic pressure ≤ 36 mmHg
but presence of additional echocardiographic variables suggestive of PH.
•Tricuspid regurgitation velocity 2.8-3.4 m/sec, PA systolic pressure 36-50 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;30:2493-2537
Pulmonary Function Testing
 Spirometry
 Lung Volumes
Often normal or
mild restriction
 Diffusion Capacity
 Mildly-moderately reduced (69% NIH study)
 Severely reduced think CVD
 Arterial Blood Gas
 Significant hypoxemia not common in IPAH unless PFO
present
Rich, Ann Intern Med 1987; 107:216
Ventilation-Perfusion Lung
Scan
Ventilation
Perfusion
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
PE
No PE
Tanariu, N. et al,
J Nucl Med, 2007
 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*
*Hofman LV, et al, AJR, 2004
Pitton MB, et al, AJR, 2007
Importance of Right Heart Cath
PAWP
LVEDP
PVR
PH
LAP
TPG
PAH (Group 1)
Hypoxic/Lung
CTEPH
CO
Fever
Thyrotoxicosis
Anemia
Pregnancy
Some PoPH
PAH
PBF
PVH
LH Disease
PV Obstruction
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
Treatment of PAH
Humbert, NEJM 2004; 351:1425
General Therapies
 Anticoagulants – only studied in IPAH
 Diuretics
 Digoxin
 Oxygen
 Salt restriction
 Rehab
Early Intervention, Regular Monitoring,
and Escalation of Treatment
Functional Capacity
No functional impairment
Late intervention
Time
Progressive remodeling
and right heart failure
in absence of treatment
Early Intervention, Regular Monitoring,
and Escalation of Treatment (cont)
Functional Capacity
No functional impairment
Will escalation of therapy and achievement of goals
improve long-term outcomes?
Early intervention
Late intervention
Time
Progressive remodeling
and right heart failure
in absence of treatment
Prostacyclin Analogues:
Oral, Intravenous, Subcutaneous, or Inhaled
Treprostinil (Remodulin®)
(Flolan®)
Epoprostenol
Treprostinil (Remodulin®)
Iloprost (Ventavis®)
Treprostinil (Tyvaso®)
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
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.
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
Epoprostenol (Flolan)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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
Treprostinil (Remodulin)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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);170-172)
1Tapson VF et al. Chest 2006;129:683-88
Iloprost
 Inhaled prostacyclin analogue
 5 mcg dose 6x per day
 5-10 minutes for inhalation
 Half-life 20-30 minutes
I-Neb
Inhaled Treprostinil (Tyvaso)
 Inhaled prostacyclin
 Administered 4 times daily
 Proprietary nebulizer
 TRIUMPH study showed
improvements in 6MWD
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 sixminute walk distance (6MWD) by +23 meters.
 Oral prostacycline receptor agonist
---Selexipag (Uptravi)—FDA approved in Dec’15
---GRIPHON study showed decrease risk of a
morbidity/mortality events compare with placebo.
Prostanoid Side Effects
 Flushing
 Hypotension
 Headache
 Dizziness
 Diarrhea, nausea,
 Syncope
vomiting
 Jaw pain
 Leg pain
 Cough (inhaled)
 Delivery site
complications
Vary according to drug and route of delivery
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
 5 - 10 mg daily
 No reported LFT abnormalities
 Pregnancy category X
 Edema main side effect
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;346:896-903
Bosentan (Tracleer)
Improved Hemodynamics
CI
Δ + 1.0 L/min/m2
(p=0.001 )
Change from baseline (%)
50%
mRAP
Δ - 6.2 mm Hg
(p=0.001)
PAP
Δ - 415dyn/sec/cm-5
(p=0.001)
Δ - 6.7 mm Hg
(p<0.02)
+4.9 ± 4.6
40%
30%
PVR
+191 ± 235
+0.5 ± 0.5
20%
+5.1 ± 8.8
10%
0%
-1.6 ± 5.1
-10%
-20%
-1.3 ± 4.1
-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
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
Sildenafil (Revatio)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
Effect of Tadalafil* on 6MWD (PHIRST)
70
Placebo
Tadalafil 2.5 mg
Tadalafil 10 mg
Tadalafil 20 mg
Tadalafil 40 mg
Change in 6MWD (m)
60
50
40
p<0.001
p<0.05
30
p<0.05
20
10
0
0
4
8
Weeks
*Adcirca®
Galiè N et al. Circulation. 2009;119;2894-2903..
12
16
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
Acute Vasodilator Testing
Kaplan-Meier Mortality
Estimates
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
Calcium Channel Blockers
Only If “Vasodilator Responsive”
“Vasodilator Response”
 Fall in mPAP ≥10 mm Hg
PLUS
 mPAP (absolute) <40 mm Hg
PLUS
 Normal or Increase CO
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Comparisons of Therapies
Cost $
(annual)
Route
Frequency
Long-term
Data
Epoprostenol
~100K
IV
Continuous
Yes
Bosentan
~65K
Oral
BID
Yes
Ambrisentan
~65K
Oral
QD
Yes
Treprostinil
>100K
SQ, IV
Continuous
Yes
Iloprost
125K
Inhaled 5-7X per day
No
Treprostinil
150K
Inhaled
QID
Yes
Tadalafil
~ 15K
Oral
QD
No
Sildenafil
~15-20K
Oral
TID
Yes
PAH (Group 1) Medication
Options
Mild
25 <MPAP< 35
• Ca++ Channel Blocker
• Endothelin antagonist
• PDE-5 inhibitor
• Prostanoids
• Inhaled iloprost
• SQ treprostinil
• IV epoprostenol
• Oral Prostaoids
X
X
X
Moderate
Severe
35 <MPAP< 50
MPAP> 50
X
X
X
X
X
X
X
X
X
X
X
X
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;369:319-29.
…other therapeutic options
 If chronic pulmonary emboli…
•
pulmonary thromboendarterectomy surgery
 If all meds fail…
•
•
atrial septostomy
organ transplantation


heart-double lung
double lung
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
LUNG TRANSPLANTATION
The only cure for PAH
100
IPAH in UNOS database
Survival (%)
75
50
N=13
25
Single Lung (N =247)
Double Lung (N=444)
N=18
P = 0.3
0
0
1
2
3
4
5
Years
6
7
8
9
10
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
Humbert, Circulation 2010; 122:156
Survival Estimates
1yr – 83%, 2 yr – 67%, 3 yr – 58%
Survival of Patients With Idiopathic PAH
According to NYHA FC at Diagnosis
100
%
survival
80
NYHA FC I/II
60
NYHA FC
III
NYHA FC IV
40
20
N=
190
0
0
12
24
36
Time (months)
FC = functional class
Humbert M, et al. Circulation. 2010;122:156-163.
Survival in PAH
1.0
Congenital heart
disease
0.9
0.8
0.7
Portopulmonary
0.6
Percent
survival
0.5
IPAH
0.4
CTD
0.3
0.2
HIV
0.1
0
0
1
2
3
Years
McLaughlin VV et al. Chest. 2004;126:78S-92S.
4
5
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
WHO functional class
IV
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
Treatment
IV prostacyclin and/or combination
treatment
I/II
> 400 m
Oral therapy
McLaughlin V et al. J Am Coll Cardiol. 2009;53:1573-1619.
Longitudinal Evaluation (cont)
Stable; no increase in
symptoms and/or
decompensation
Clinical course
Unstable; increase in
symptoms and/or
decompensation
Frequency of
evaluation
Every 1-3 months
Every clinic visit
Functional class
assessment
Every clinic visit
Every clinic visit
6MW distance
Every clinic visit
Echocardiography
Every 6-12 months or center
dependent
BNP
Center dependent
Right heart
catheterization
Every 6-12 months or clinical
deterioration
Every 3-6 months
Every 12 months or center
dependent
Center dependent
Clinical deterioration and
center dependent
McLaughlin V, et al. J Am Coll Cardiol. 2009;53:1573-1619.
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
What is the most common cause of pulmonary
hypertension?
1.
2.
3.
4.
Left heart failure
Connective tissue disorder
Idiopathic
Pulmonary embolism
An echocardiogram is not adequate to diagnose
pulmonary arterial hypertension.
1.
2.
True
False
Calcium channel blockers are considered first line
therapy for pulmonary arterial hypertension.
1.
2.
True
False
Prostacyclins are the last option that should be used to
treat pulmonary arterial hypertension.
1.
2.
True
False
Oral or inhaled medication shouldn’t be used in class IV
1. True
2. False
Anticoagulation should be used only in IPAH
1. True
2. False