Upload
others
View
14
Download
0
Embed Size (px)
Citation preview
Pulmonary Hypertension for the Internist
Lana Melendres-Groves MD Director Pulmonary Hypertension Program
University of New Mexico Health Science Center 11/04/16
Disclosures
• Consultant and member of the Speaker Bureaus for Actelion Pharmaceuticals, Gilead Pharmaceuticals, and Bayer Pharmaceuticals.
Objectives
• Define pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH)
• Describe the pathophysiology/pathobiology of PAH
• Discuss the classification system of PH • Discuss detection and diagnosis of PH and PAH • Review general and acute care management of
PH • Discuss PAH specific medical therapies briefly
Case #1
• 38yo woman with progressive shortness of breath over the past year. Now, unable to perform her daily activities without assistance. Currently requiring 4 liters of oxygen.
• PMHx significant for chronic renal insufficiency
• Presenting to her PCP for further work-up.
Definition of PH
• PH refers to the presence of abnormally high pulmonary vascular pressure
Normal mPAP: 8-20mmHg at rest
PH Defined: mPAP> 25mmHg at rest
WHO Classification System for PH
• Group 1: Pulmonary Arterial Hypertension (PAH)
• Group 2: PH due to left heart disease • Group 3: PH due to lung disease and/or
hypoxia • Group 4: Chronic thromboembolic pulmonary
hypertension • Group 5: PH with unclear multifactorial
mechanisms
Clinical Classification of Pulmonary Hypertension (NICE, 2013)
1. Pulmonary arterial hypertension (PAH) 1.1 Idiopathic PAH (IPAH) 1.2 Heritable PAH 1.3 Drug- and toxin-induced PAH 1.4 Associated PAH 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1’. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemagiomatosis (PGH) 1”. Persistent pulmonary hypertension of the newborn (PPHN) 2. PH due to left heart disease 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
3. PH due to lung disease and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary disease with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 4. Chronic thromboembolic hypertension (CTEPH) 5. PH with unclear multifactorial mechanisms 5.1 Hematologic disorders 5.2 Systemic disorders 5.3 Metabolic disorders 5.4 Others
Simonneau G, et al. J AmColl Cardiol. 2013;62(25, suppl D);D34-D41
Mixed PH
Pre-capillary PH High-flow PH (O2 sat run)
Hemodynamic Classification of PH (mean PAP >25 mm Hg)
VC RA RV PA PV PC
LA LV Ao
Post-capillary PH
Diagram courtesy of Teresa De Marco, MD, UCSF
Hemodynamic Classification of PH (mean PAP >25 mm Hg)
VC RA RV PA PV
↑PVP PC
LA
↑LAP
LV Ao
↑LVEDP
Post-capillary PH PCWP>15 mm Hg; PVR normal
Diagram courtesy of Teresa De Marco, MD
Hemodynamic Classification of PH (mean PAP >25 mm Hg)
VC RA RV PA PV
↑PVP PC
LA
↑LAP
LV Ao
↑LVEDP
Post-capillary PH PCWP>15 mm Hg; PVR normal
Diagram courtesy of Teresa De Marco, MD
Systemic HTN AoV disease Myocardial Disease
Dilated CMP-ischemic/non-ischemic Hypertrophic CMP Restrictive/infiltrative CMP Obesity related CMP Pericardial disease
MR
Hemodynamic Classification of PH (mean PAP >25 mm Hg)
VC RA RV PA PV PC
LA LV Ao
Pre-capillary PH PCWP <15 mm Hg;
PVR >3 woods units
{
{
PAH Lung diseases +/- hypoxemia
CTEPH
Diagram courtesy of Teresa De Marco, MD
Presence of PH Worsens Outcomes Across All Groups
WHO Group 1 PAH
WHO Group 2 Left-heart related
WHO Group 3 Lung/hypoxia related
WHO Group 4 CTEPH
Based on a sample of 194 patients
followed between 1981 and 1986, median survival
was estimated at 2.8 years (IPAH)
In a study of 379 patients referred to a single center between 1992
and 1998, patients with Group 2 PH
had 7x higher mortality than left-sided heart failure
alone
5-year survival rate in a study of 84
COPD patients was 62% in patients
without PH and only 36% in those with PH
In a study of 79 IPF patients, the 6.5-year survival rate was 40% among those with PH vs
70% in patients with IPF alone
Mean survival 6.8 years without surgical
intervention in a study of 48
Japanese patients versus 75% survival at >6 years post-
PTE
Case #2
• 28yo woman from rural New Mexico presenting to the ER for chest pain. Experiencing progressive fatigue and shortness of breath after the birth of her child 10 months ago.
• PMHx: none • Work-up in unremarkable presenting to her
PCP for follow-up.
Pulmonary Arterial Hypertension
A further look into WHO Group 1
How is PAH Defined
• PAH is a syndrome resulting from restricted blood flow in the pulmonary arterial circulation resulting in increased pulmonary vascular resistance which causes right ventricular strain and ultimately failure.
Hemodynamic - mPAP >25mmHg definition of PAH: - PCWP <15mmHg - PVR > 3 wood units
Pathogenesis of PAH: Aberrant Pathways
Loss of Biological “Balance” in PAH
Vasodilation Apoptosis
Vasoconstriction Proliferation
Vasodilation Apoptosis
Vasoconstriction Proliferation
SMC
Endothelium elastic lamina injury
Injury serum leak
SMC PROLIFERATION & MIGRATION
Pathobiology of PAH
Pulmonary Arterial Hypertension
1.1 Idiopathic PAH (IPAH) 1.2 Heritable PAH 1.3 Drug- and toxin-induced PAH 1.4 Associated PAH 1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis
Prevalence of PAH in Connective Tissue Diseases
Systemic lupus erythematosis (SLE): 0.5% to 17% Mixed Connective tissue disease (MCTD): up to 25%
Systemic Sclerosis: 8% to 27%
SLE
MCTD
Systemic Sclerosis
Drugs and Toxins Associated with PAH
Definite - Aminorex - Fenfluramine - Dexfenfluramine - Toxic rapeseed oil - Benfluorex - Dasatinib
Likely - Amphetamines - L-tryptophan - Methamphetamines
Possible - Cocaine - Phenylpropanolamine - St. John’s Wort - Chemotherapeutic
agents - SSRI* - Pergolide
Unlikely - Oral contraceptives - Estrogen - Cigarette smoking
* Related to persistent pulmonary hypertension of the newborn
Drugs and Toxins Associated with PAH
Definite - Aminorex - Fenfluramine - Dexfenfluramine - Toxic rapeseed oil - Benfluorex - Dasatinib
Likely - Amphetamines - L-tryptophan - Methamphetamines
Possible - Cocaine - Phenylpropanolamine - St. John’s Wort - Chemotherapeutic
agents - SSRI* - Pergolide
Unlikely - Oral contraceptives - Estrogen - Cigarette smoking
* Related to persistent pulmonary hypertension of the newborn
PAH associated with Portal Hypertension
• Prevalence of PAH in portal htn ranges from 2% to 6%
• Risk of developing PAH increases with duration of portal hypertension
• Liver disease is the most common cause of portal hypertension, but it can be secondary to nonhepatic causes
• Portal pulmonary hypertension plays a significant part in transplant candidacy
Time
PAP PVR
CO
Pre-symptomatic Compensated
Symptomatic Decompensating
RV Failure
Declining Decompensated
CO α PAP
PVR
Schematic Progression of PAH
Case #3
• 62yo man h/o htn referred to pulmonary for progressive dyspnea. Now, unable to work.
• Prior smoking history, quit 5 years ago • PFT’s reported as normal but no records
available • Exam significant for a holosystolic ejection
murmur at the LLSB • Bilateral lower extremity edema present
What does a PH patient look like
Symptoms
• Breathlessness • Chest pain • Dizziness • Syncope • Loss of energy • Edema • Dry cough
Physical Exam • Increased jugular venous
pressure • Accentuated split S2 • Presence S3 • TR murmur- heard best LL
sternal border • Edema and/or ascites • Hepatojugular reflux • Skin- telangiectasias,
Raynaud’s, Sclerodactyly
McGoon et al. Chest 2004;126:14S-34S
No further evaluation
for PAH
Is PAH likely? Echo
Is there a reason to suspect PAH Clinical history (symptoms, risk factors, family Hs.),
Exam, CXR, ECG
Is PAH due to LH disease? Echo
Is PAH due to CHD? Echo with contrast
Is PAH due to CTD, HIV? Serologies
Dx Scleroderma, SLE, other CTD, HIV: Medical treatment of PAH and further evaluation for
other contributing causes, including RHC
Dx abnormal morphology; shunt: Surgery. Medical treatment of PAH or evaluation for
further definition or other contributing causes, including R&LHC if necessary
Dx LV systolic, diastolic dysfunction; valvular disease: Appropriate treatment and further evaluation
if necessary, including R&LHC
TRV to measure RVSP; RVE; RAE; RV Dysfunction:
yes
yes
yes
Rationale
no
no
no
yes
yes no
no
PAH: Detection and Diagnosis
Is chronic PE suspected? VQ scan
McGoon et al. Chest 2004;126:14S-34S
Dx parenchymal lung disease, hypoxemia, or sleep disorder: Medical treatment, oxygen, positive pressure breathing
as appropriate, and further evaluation for other contributing causes, including RHC if necessary
yes
Document exercise capacity regardless of cause of PH: Establish baseline, prognosis and document progression/
response to treatment with serial reassessments
Document PA and RA pressures, PCWP (LV or LA pressure if PCWP unobtainable or uncertain), transpulmonary gradient
CO, PVR, SvO2, response to vasodilators: Confirm PAH, or IPAH if no other cause identified
Discuss genetic testing and counseling of IPAH
What limitations are caused by the PAH?
Functional class; 6-minute walk test
What are the precise pulmonary hemodynamics?
RHC
Is chronic PE suspected? VQ scan
Is PAH due to lung disease or hypoxemia?
PFTs, arterial saturation
Is chronic PE confirmed and operable? Pulmonary angiogram
Anatomic definition (CT, MRI may provide additional useful but not definitive information):
Thromboendarterectomy if appropriate or medical treatment; clotting evaluation; a/c
yes yes
no
no
no VQ normal
PAH: Detection and Diagnosis
Right Heart Catheterization: Diagnostic Gold Standard
• Hemodynamics: – RAP, mPAP, PCWP, CO/CI, PVR
• Saturations: – Rule out shunts
• Angiography: – Vessel properties – CTEPH
• Vasodilator response
Case #4
• 52yo woman with obesity, depression and worsening fatigue. Recently started on anti-depressant. Continues to work as a hairdresser.
• Work-up thus far shows normal basic lab work.
• Patient returning for follow-up, now concerned about intermittent dizziness with minimal exertion and some chest discomfort.
We have a diagnosis, now what?
Survival After Diagnosis
2.8 Years
3.9 Years
5.5 Years
7 Years
0
2
4
6
8
1980s 1990s 2000s 2010s
Estim
ated
Med
ian
Surv
ival
(Y
ears
)
D'Alonzo GE, et al. Ann Intern Med. 1991:115:343-349; Thenappan T, et al. Eur Respir J. 2010;35:1079-1087; Humbert M, et al. Eur Respir J. 2010;36:549-555; Benza RL, et al. Chest. 2012;142:448-456
Importance of Accurate Diagnosis
• RePHerral study: – Multicenter, descriptive, cross-sectional study – Consisting of 140 patients – Performed to determine:
• accuracy of PH diagnoses in patients referred to PH centers • frequency of PAH-specific medication use despite an uncertain or
incorrect diagnosis.
• Results indicated that 33% of patients diagnosed with PAH upon referral had an incorrect diagnosis.
• 42% did not have a confirmatory heart catheterization at the time of referral
Deano RC, et al. JAMA Intern Med 2013; 173: 887-893
WHO Functional Class is a Symptom-Based Indicator of Disease Severity
Class Functional Classification of Patients with PAH
I No limitation of usual physical activity, ordinary physical activity does not cause increased dyspnea, fatigue, chest pain, or pre-syncope
II Slight limitation of physical activity. No discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or pre-syncope
III Marked limitation of physical activity. No discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or pre-syncope
IV Unable to perform any physical activity and possible signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity.
Functional Assessment
• Functional assessment is key to appropriate therapeutic approach – WHO functional class (WHO I-IV)
• The RePHerral study indicated that at the time of referral, more than half of all 140 patients had functional class III and IV disease (62%) – REVEAL registry showed a mortality of 50%
at 2 years for class IV patients
Deano RC, et al. JAMA Intern Med 2013; 173: 887-893
Case #5
• 41yo woman with admitted early in the year for hypoxia and treated for pna.
• Presenting for hospital follow-up to her PCP to see if she can get off the oxygen s/p discharge.
• Hasn’t been able to get back to her prior baseline energy level or activity level with ongoing SOB.
• PFTs normal, CXR normal, lab work normal.
Bringing it All Together:
General and Acute Care of the Pulmonary Hypertension
Patient
General and Acute Care in PH
• Approximately 658,000 ED encounters annually in the US are primarily due to heart failure.
• 3-9% of those are due to acute right ventricular failure (RVF) – 20-60 thousand encounters
• Recent study estimates more than 64,400 ED visits in the US, over 5 years, were due to PAH patients – Few studies to guide the management of PH or RVF in
the acute setting
Stein et al. Scope of the problem of PAH. Am J Med. 2015
Assessing a PH Patient
• Identifying the signs and symptoms of decompensated right heart failure. – Edema, ascites, sob, chest pain, arrhythmias – EKG, CXR, bedside echo
• Understanding the cause of PH to appropriately treat – Group 1 versus groups 2-5
PH/PAH General Care • Fluid/volume control
• Oxygen
• Anticoagulation
• Underlying Diseases
• Diuretics • Low sodium diet • Daily weights/I&Os • Hypoxia is a potent
vasoconstrictor and can elevate PA pressure
• CTEPH patients life-long anticoagulation
• Optimization of their other diseases
• Drug screening
Right Ventricular Failure Management Considerations
• RV failure in PAH (Group 1): – Continue/resume pulmonary vasodilator regimen – Early consultation with PH specialist – Consider risks of volume overload (no large
volume boluses) – Provide hemodynamic support with inotropes,
vasopressors, pulmonary vasodilators as indicated – Consider early referral for more specialized
treatments
RV Failure Management Considerations
• RV failure in other types of PH (Group 2-5) – Aggressively treat underlying condition, such as
diuresis for PH from left-sided heart failure or bronchodilators for PH from COPD
– Correct hypoxemia and respiratory acidosis – Consider ionotropic support as indicated, with
norepinephrine as a first-line agent – Early consultation with cardiology, pulmonary, or
PH specialist – For CTEPH, emergency referral to expert center
Pharmacologic Therapies for the Maintenance of PAH
Therapeutic Pathways
Introduction of PAH Therapies
Mid-80’s
•Conventional therapy
1995
•Prostanoids introduced
2001
•ERAs introduced
2005
•PDE-5is introduced
2013
•sGC introduced
2016
•Oral prostanoid analog
Current
•Continued exploration of new treatment strategies
FDA Approved PAH Therapies
• Prostanoid/Prostanoid Analogs – Epoprostenol (flolan/veletri) – Treprostinil (IV/SQ/Inhaled) – Inhaled Iloprost (Ventavis) – Oral treprostinil (Orenitram) – Selexipag (Uptravi)
• PDE-5 Inhibitors – Sildenafil (Revatio) – Tadalafil (Adcirca)
• ERA’s – Bosentan (Trecleer) – Ambrisentan (Letairs) – Macitentan (Opsumit)
• Soluable Guanylate Cyclase Stimulator – Riociguat (Adempas) (Only medication currently approved for the use in CTEPH)
Therapies
• The only groups that have been approved for the specialized medications for pulmonary hypertension are WHO Group 1 (PAH) and Group 4 (CTEPH)
• The WHO Group 2, 3, and 5 require treatment of the underlying condition or optimization of that condition
Treatment Recommendations
• Despite ongoing updated therapeutic guidelines (most recently from 2015 in ESC/ERS), there is still a substantial problem with inappropriate prescribing of PAH therapies.
• 57% of the RePHerral study patients who had been prescribed PAH-specific medications prior to referral, showed treatment guidelines had not been adhered to Galiè N, et al. Eur Heart J. 2016; 37:67-119; Galiè N, er al. Eur Respir J., 2015; 46:903-975
Treatment Recommendations
• Even when there is a Grade 1A recommendation: Epoprostenol IV/SQ for functional class IV PAH patients
• REVEAL registry showed that at time of death for these WHO class IV patients, 42% had still not received appropriate therapy
• Increasing evidence for sequential and dual upfront combination therapy
Ongoing Management
• The standard of care for PAH patients is establishment with a PH Care Center – Multidisciplinary approach to care – PHA initiative to standardized care through CCC and
RCC (currently 37 in the US) • Patients on advance therapies to be seen every 3
months if not more frequently • Ongoing escalation of care, more evidence
coming out showing the importance of up-front combination therapies.
Back to the Cases
• Case #1: 38yo woman CRF and NYHA class 4 symptoms on 4 liters oxygen with SOB.
• Case #2: 28yo woman with 10months old who has chest pain and sob.
• Case #3: 62yo man with DOE, former smoker now with increasing LEE.
• Case #4: 52yo woman with obesity, depression and profound fatigue now with episodes of dizziness.
• Case #5: 41yo woman with pna discharged on oxygen with ongoing fatigue and now CP.
What do you think?
• Do any of the patients have PH? • Do any of the patients have PAH? • They all have PH and 4 of them have PAH:
– Patient #1: found to have CTEPH, underwent PTE – Patient #2: PAH associated with CHD from ASD – Patient #3: PAH associated with CTD – Patient #4: PAH associated with drugs and toxins – Patient #5: IPAH
Discussion
• PH is an umbrella term that encompasses a multitude of disease processes. – Simply a hemodynamic definition
• Classification of PH includes 5 WHO groups • The pathobiology for PAH is the same no matter
the underlying etiology: 3 pathways • PH is screened with an echo and diagnosed with
RHC • Management is multifactorial and requires a
multidisciplinary approach to care.
Questions?