Download A Practical Approach to Pulmonary Hypertension

A Practical Approach to Pulmonary
Hypertension
Brittany Palmer, M.D.
Outline
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•
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•
•
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PH definition and classification
Pathogenesis
Patient assessment
Making the diagnosis
Therapeutic options and efficacy
Summary
Pulmonary Arterial Hypertension:
Definition
• Mean PA pressure > 25 mmHg with PCW
<15 mmHg
– (NIH Registry on PPH, 1987)
• PVR ≥ 3 Units
PVR = TPG/CO
TPG = PAM-PCW
• Exercise mean PA pressure > 30-35 mmHg
Clinical classification of pulmonary
hypertension (Nice 2013)
1.
Pulmonary arterial hypertension
– Idiopathic PAH
– Heritable PAH (BMPR2, ALK1)
– Drug and Toxin induced
– Associated with:
•
•
•
•
•
Connective tissue disease
Congenital heart disease
Portal hypertension
HIV infection
Schistosomiasis
2. PH with left heart disease
Systolic or diastolic dysfunction
Valvular
Congenital/acquired left heart
inflow/outflow tract obstruction and
congenital cardiomyopathies
1’. PVOD/PCH
Simonneau G, et al. J Am Coll Cardiol. 20013;62(25_S)
Clinical classification of pulmonary
hypertension (Nice 2013)
3. PH with lung diseases/hypoxemia
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•
•
•
•
•
COPD
Interstitial lung disease
Sleep-disordered breathing
Developmental abnormalities
Mixed restrictive/obstructive
Alveolar hypoventilation
5. Miscellaneous
Pulmonary hypertension with unclear multifactorial
mechanisms
Hematologic disorders: myeloproliferative
disorders, splenectomy, chronic hemolytic anemia
Systemic disorders: sarcoidosis, pulmonary
histiocytosis, lymphangioleiomyomatosis
Metabolic disorders: glycogen storage disease,
Gaucher disease, thyroid disorders
Others: tumoral obstruction, fibrosing mediastinitis,
chronic renal failure, segmental PH
4. PH due to chronic thrombotic
and/or embolic disease
•
CTEPH
Simonneau G, et al. J Am Coll Cardiol. 2013;62(25_S)
Pathogenesis of
Pulmonary Arterial Hypertension
NORMAL
Gaine, JAMA 2000;284:3164
REVERSIBLE DISEASE
IRREVERSIBLE DISEASE
Percentage Surviving
A Disease of Decline & Deterioration
IPAH Survival
100
NIH Registry
Sitbon Historical Control
ACCP Estimate
80
60
40
20
0
0
0.5
1
1.5
2
2.5
3
3.5
Years of Follow-up
Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788.
Adapted from: D’Alonzo GE,. Ann Int Med 1991;115:343-349
Adapted from: McLaughlin et al. CHEST; 126: 78S-91S
4
4.5
5
Assessment of PAH:
Signs and Symptoms
• Initial signs and symptoms
- Dyspnea
- Fatigue
- Syncope
- Edema
- Dizziness
- Angina
• Non-specific nature of complaint can lead
to:
- Confusion with other conditions
- Delayed diagnosis
Assessment of PAH:
Physical Exam
Presence of PH
Presence of RV Failure
• Loud P2
• JVD with V wave
• RV lift
• RV S3
• Systolic murmur (TR)
• Hepatomegaly
• Diastolic murmur (PR)
• Edema
• RV S4
• Ascites
Assessment of PAH:
CXR
Peripheral Hypovascularity
(Pruning)
RV Enlargement into
Retrosternal Clear Space
Prominent Hilar
Pulmonary Arteries
Assessment of PAH:
EKG
RAD
RVH
RAE
RV Strain
McGoon M et al for the American College of Chest Physicians. Chest. 2004;126:14S-34S.
PAH: Making the Diagnosis
Is There A Reason to Suspect PAH?
Clinical History (Symptoms, Risk Factors), Exam, CXR, ECG
No
No Further
Evaluation
Yes
Is PH Likely?
ECHO
Rationale
TR Velocity to Measure RVSP,RVE,
RAE, RV Dysfunction
Yes
Is PH Due to LH Disease?
ECHO
McGoon M et al for the American College of Chest Physicians. Chest. 2004;126:14S-34S.
Echocardiogram:
Parasternal Long Axis
Image courtesy of Vallerie McLaughlin, MD
Echocardiogram:
Parasternal Short Axis
Image courtesy of Vallerie McLaughlin, MD
Echocardiogram:
Apical Four Chamber
Image courtesy of Vallerie McLaughlin, MD
Echocardiogram:
Tricuspid Regurgitation
Modified Bernoulli’s Equation:
4 x (V)² + RAP = RVSP (PASP)
V=tricuspid jet velocity (m/s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure;
PASP=pulmonary artery systolic pressure.
Image courtesy of Vallerie McLaughlin, MD
PAH: Making the Diagnosis
Is There A Reason to Suspect PAH?
Clinical History (Symptoms, Risk Factors), Exam, CXR, ECG
No
No Further
Evaluation
Yes
Is PH Likely?
ECHO
Rationale
TR Velocity to Measure RVSP,RVE,
RAE, RV Dysfunction
Yes
Is PH Due to LH Disease?
ECHO
Yes
Dx LV Systolic, Diastolic Dysfunction;
Valvular Disease: Appropriate Treatment
Yes
Dx Abnormal Morphology; Shunt:
Surgery, Medical Treatment of PAH or Further
Evaluation for Other Contributing Causes
Yes
Dx Scleroderma, SLE, HIV Infection:
Medical Treatment of PAH and Further Evaluation for
Other Contributing Causes
No
Is PH Due to CHD?
ECHO With Bubble Study
No
Is PH Due to CTD, HIV?
Serologies
No
Is Chronic PH Suspected?
VQ Scan
McGoon M et al for the American College of Chest Physicians. Chest. 2004;126:14S-34S.
Ventilation Perfusion Lung Scan
Idiopathic
Pulmonary
Arterial
Hypertension
Perfusion
Ventilation
Chronic
Pulmonary
Embolism
Perfusion
Ventilation
Contrast-Enhanced CT
Is Chronic PE Confirmed
and Operable?
Bands
Pouch
Absent
branches
PAH: Making the Diagnosis
Is PH Due to Lung Disease?
PFTs, Arterial Saturation
Yes
Dx Parenchymal Lung Disease, Hypoxemia, or
Sleep Disorder: Medical Treatment, Oxygen, Positive
Pressure Breathing As Appropriate, and Further Evaluation for
Other Contributing Causes
No
What Limitations Are Caused by the PH?
Functional Class; 6-minute Walk Distance Test
(6MWD)
What are precise pulmonary hemodynamics?
RHC
Document Exercise Capacity Regardless of Cause of PH:
Establish Baseline, Prognosis and Document
Progression/response to Treatment With Serial
Reassessments
Document PA pressure, PCWP (LV or LA pressure if
PCWP unobtainable or uncertain), transpulmonary
gradient, CO, PVR, MVO2, response to vasodilators:
Confirm PAH, or IPAH if no other cause identified
McGoon M et al for the American College of Chest Physicians. Chest. 2004;126:14S-34S.
PAH Definition on RHC
• Increased mean pulmonary arterial pressure (mPAP)
– >25 mm Hg at rest or >30 mm Hg during exercise
• Pulmonary vascular resistance (PVR): >3 WU
• Normal PCWP (<15 mm Hg)
Definition
Characteristics
Clinical group
Pre-capillary PH
Mean PAP ≥25 mm Hg
PWP ≤15 mm Hg
CO normal or reduced
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


Post-capillary PH
Mean PAP ≥25 mm Hg
PWP >15 mm Hg
CO normal or reduced
Passive = TPG ≤12 mm Hg
Reactive = TPG >12 mm Hg
Adapted from: Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.

Pulmonary arterial
hypertension
PH due to lung disease
CTEPH
PH with unclear or
multifactorial mechanisms
PH due to left heart disease
Progression of PAH
Pre-symptomatic/
Compensated
CO
Symptomatic/
Decompensating
Declining/
Decompensated
Symptom Threshold
PAP
PVR
Right Heart
Dysfunction
Time
Therapeutic Options for PAH
Traditional Rxs
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•
•
•
•
Supplemental O2
Diuretics
Oral vasodilators
– (CCB)
Anticoagulants
– warfarin
Inotropic agents
– Digitalis
•
•
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FDA Approved for PAH
Investigational Rxs
Prostanoids
– Epoprostenol (iv)
– Treprostinil (iv, sq, inh)
– Iloprost (inhaled)
ERAs
– Bosentan
– Ambrisentan
– Macitentan
PDE-5 Inhibitors
– Sildenafil
– Tadalafil
•
•
•
Prostanoids
– Oral Treprostinil
ERAs
– Sitaxsentan
Other
- TKIs
- sGC stimulator
- Prostacyclin
receptor agonist
PAH Determinants of Risk
Lower Risk
Determinants of Risk
Higher Risk
No
Clinical evidence of
RV failure
Yes
Gradual
Progression
Rapid
II, III
WHO class
IV
Longer (>400 m)
6MW distance
Shorter (<300 m)
Minimally elevated
BNP
Very elevated
Minimal RV dysfunction
Echocardiographic
findings
Pericardial effusion,
significant RV
dysfunction
Normal/near normal
RAP and CI
Hemodynamics
High RAP, low CI
McLaughlin and McGoon. Circulation 2006;114:1417-31
ADULT LUNG TRANSPLANTATION
Kaplan-Meier Survival By Diagnosis (Transplants: January 1994 – June 2003)
100
)N=1,127(ALPHA-1
)N= 4,888(COPD
)N= 533(PPH
)N= 1,934(CF
)N= 2,058(IPF
)N = 314(SARCOIDOSIS
Survival (%)
75
50
Survival comparisons
COPD vs. IPF: p < 0.0001
Alpha-1 vs. CF: p = 0.0248
Alpha-1 vs. IPF: p < 0.0001
Alpha-1 vs. PPH: p = 0.0021
CF vs. COPD: p = 0.0006
CF vs. IPF: p < 0.0001
HALF-LIFE Alpha-1: 5.1 Years; CF: 5.8 Years; COPD: 4.8
CF vs. PPH: p < 0.0001
CF vs. Sarcoidosis: p = 0.0007 Years; IPF: 3.7 Years; PPH: 4.3 Years; Sarcoidosis: 4.0 Years
25
0
0
1
2
3
4
5
6
7
8
9
Years
J Heart Lung Transplant 2005;24: 945-982
10
Key Concept Summary
• Differential Diagnosis
–
–
–
–
Beware of the atypical patient
Process of Diagnosis of Exclusion
CTEPH - “curable”
Associated “risk factors”
• Treatment
–
–
–
–
–
–
–
Prostanoids
Endothelin Receptor Antagonism
Phosphodiesterase Inhibitors
Riociguat
Anticoagulation
RV Failure
Transplant
Thank you
Hemodynamic Profiles In PAH: LV
dysfunction – “passive” PH
C.O. 4 L/min
TPG = 7
100
PVR = 1.75
80
45/5
60
45/25
32
25
40
20
5
0
RA
RV
PA
PA
PCW
Hemodynamic Profiles In PAH: LV
dysfunction – after Rx
C.O. 5 L/min
TPG = 6
100
PVR = 1.2
mmHg
80
60
20/2
20/8
12
6
40
20
2
0
RA
RV
PA
PA
PCW
Hemodynamic Profiles In PAH:
IPAH - compensated
C.O. 5 L/min
TPG = 40
100
80/15
80/40
52
PVR = 8
80
60
40
20
10
12
0
RA
RV
PA
PA
PCW
What is the Optimal Treatment Strategy?
Anticoagulate ± Diuretics ±
Oxygen ± Digoxin
Acute Vasoreactivity Testing
Negative
Positive
Lower
Class Risk
II-III
Oral CCB
No
Sustained
Response
ERAs or PDE-5 Is (oral)
Epoprostenol or Treprostinil (IV)
Iloprost (inhaled)
Treprostinil (SC)
Higher
Class III-IV
Risk
Epoprostenol or Treprostinil
(IV)
Iloprost (inhaled)
ERAs or PDE-5 Is (oral)
Treprostinil (SC)
Yes
Continue
CCB
Reassess – consider
combo-therapy
Investigational
Protocols
Modified from Badesch DB et al. Chest. 2004;126:35S-62S.
Atrial septostomy
Lung Transplant
PAH
Basic therapy
Oral anticoagulants, Diuretics, O2, Digoxin ...
Acute vasoreactivity test
Positive
Oral CCB
Sustained
Response
Yes
Negative
No CCB +++
Fall in mPAP > 10 mmHg
+ mPAP < 40 mmHg
+ Normal CO
Close monitoring of long-term clinical and hemodynamic effects
Continue
CCB
Sitbon O, et al. Circulation. 2005;111:3105-3111.
3rd World PAH Symposium. J Am Coll Cardiol 2004;43:1S-90S.
ACCP Guidelines. Chest 2004;126:1S-92S.
Galiè N, et al. ESC Guidelines. Eur Heart J 2004;25:2243-78.
Survival in IPAH
Long-term CCB Responders
1.0
Long-term CCB responders
(~50% of acute responders or ≤6% of
iPAH patients)
P=0.0007
0.8
Cumulative
survival
0.6
Long-term CCB failure
0.4
0.2
0.0
0
Subjects
at risk, n
2
4
6
8 10 12 14
(Years)
38
33
30
22
13
19
12
7
4
0
Sitbon O et al. Circulation. 2005;111:3105-3111.
8
3
3
16 18
2
1
Long-term CCB
responders
Long-term CCB
failure
Prostacyclins
• Epoprostenol
• Treprostinil
• Iloprost
Epoprostenol (Flolan®)
• FDA-approved for Class III-IV PAH
• Chemically unstable, short half life
• Continuous IV Rx
• Significant SE’s
• Line complications
Treprostinil (Remodulin®)
• FDA-approved for Class II-IV PAH
• Chemically stable; longer half-life
• Continuous SQ or IV; inhaled (Tyvaso)
• oral under investigation
• Smaller pump
• Typical prostanoid SE’s
• SQ limited by site pain
Iloprost (Ventavis®)
•
•
•
•
•
•
FDA-approved for Class II-IV PAH
Chemically stable; longer half-life
Inhaled (6-9 times daily)
• IV in Europe
Typical )? milder( prostanoid SE’s
? Favored for patients with parenchymal lung
disease:
• Provides prostacyclin activity directly to lung
• Vasodilates (only?) ventilated pulmonary
regions
Avoids catheter complications
IV Epoprostenol in IPAH: Change From Baseline in
6MW Test
40
30
31
20
Median change 10
from baseline
0
(m)
P<0.002
-10
-20
-30
Epoprostenol
(n=41; baseline=315 m)
Barst RJ et al for the PPH Study Group. N Engl J Med. 1996;334:296-301.
-29
Conventional
(n=40; baseline=270 m)
Long-term Outcome in IPAH With Epoprostenol
Cumulative Survival
% Survival
1
100
Observed (n=162)
0.8
80
*
0.6
IV Epoprostenol
(n=178)
*
60
0.4
*
P<0.0001
0.2
Historical Control
(n=135)
0
Expected
40
*P<0.001
20
0
12
24
36 48
60 72 84
Months
96 108 120
No. at risk:
178 129 85 57 36 21
7
3
1
IV Epoprostenol
135 59 34 20 11
2
2
1
Historical Control
4
McLaughlin VV et al. Circulation. 2002;106:1477-1482.
Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788.
0
6
12
18
24
Months
30
36
Subcutaneous Treprostinil: Change From
Baseline in 6MW Test by Dose Quartile
50
36.1±10
40
Mean change
from baseline
(m)
20±8
30
20
3.3±10
10
0
1st Quartile
<5
(n=45)
1.4±9
2nd Quartile
3rd Quartile
5 to <8.2
8.2 to <13.8
(n=55)
(n=49)
ng/kg/min
Simonneau G et al. Am J Respir Crit Care Med. 2002;165:800-804.
4th Quartile
>13.8
(n=53)
Inhaled Iloprost: Change from Baseline in 6MW Test
(AIR Trial)
40
30
Placebo (n=102)
Iloprost (n=101)
P=0.004
20
Mean change
from baseline
(m)
10
0
-10
-20
-30
-40
Week 4
Week 8
AIR=Aerosolized Iloprost Randomized.
6MW test was not the primary endpoint in the AIR trial.
Olschewski H et al for the Aerosolized Iloprost Randomized Study Group. N Engl J Med. 2002;347:322-329.
Week 12
Endothelin Receptor Antagonists
- FDA approved for class III-IV PAH
- Fluid retention
- Oral, well-tolerated
- Teratogens
• Bosentan (Tracleer)
• Mixed ETA/ETB antagonist
• BID
• LFTs
• Ambrisentan (Letairis)
• ETA specificity
• Unique metabolism, ? lack of drug-drug interaction
• Once daily
Bosentan: 6-Minute Walk Test
Mean change from baseline (m)
Study 351
100
BREATHE-1
60
Bosentan
(n=21)
80
Bosentan
(n=144)
40
60
40
20
P=0.0002
20
0
0
-20
Placebo
(n=11)
-40
-20
-60
Baseline
Placebo
(n=69)
-40
4
8
12
Week
20
Baseline
4
8
Week
Values are mean±SEM.
Channick RN et al. Lancet. 2001;358:1119-1123.
Rubin LJ et al for the Bosentan Randomized Trial of Endothelin Antagonist Therapy Study Group.
N Engl J Med. 2002;346;896-903.
16
PDE 5 Inhibitors
• Sildenafil (Viagra, Revatio)
• FDA approved for class II-IV PAH
• Oral, well-tolerated
• Usual PDE 5 inhibitor concerns
• Tadalafil (Cialis, Adcirca)
• Once daily
Sildenafil: Change from Baseline in 6MW Test
80
*
*
46 m
60
45 m
*P<0.001
*
Mean change
from baseline 20
(m)
0
Week 4
Week 8
Week 12
-20
-40
Placebo (n=65)
Sildenafil 20 mg tid (n=65)
Sildenafil 40 mg tid (n=63)
Sildenafil 80 mg tid (n=65)
Galiè N et al for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. N Engl J Med.
2005;353:2148–2157.
50 m
40
New Directions in PAH
• New treatments
• New delivery strategies
• Treprostinil, reformulated Iloprost
• Drug combos
• FREEDOM, COMPASS 2 (and many more)
• New assessments
• Genomics/proteomics/etc.
• RV studies
• New (related) disease states
• Groups II, III, IV and V
Pregnancy in PAH
• Maternal death rate is 30-50%
• Majority of deaths occur in the first week
following delivery
• Maternal mortality increased by
hypovolemia, thromboemboli, and preeclampsia/eclampsia
• Poor fetal outcome with only 25% of all
pregnancies reaching term