Pulmonary Hypertension - UTAH AFP...Pulmonary Hypertension @drjohnjryan John J. Ryan, MD Director, Pulmonary Hypertension Center University of Utah, Division of Cardiovascular Medicine
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Pulmonary Hypertension @drjohnjryan John J. Ryan, MD Director, Pulmonary Hypertension Center University of Utah, Division of Cardiovascular Medicine. 2019 UAFP CME-n-Ski Conference February 22 nd 2019 @drjohnjryan @JJRyanMD
John J. Ryan, MDDirector, Pulmonary Hypertension Center
University of Utah, Division of Cardiovascular Medicine.
2019 UAFP CME-n-Ski ConferenceFebruary 22nd 2019
@drjohnjryan@JJRyanMD
Presenter
Presentation Notes
Thank you for having me. Thank you to Vinicio and Bob for inviting me out. I am a mountain doctor. As an Irish man, I never thought I would move to Utah! But we started the PH program there about 3 years ago. The main concern that we have in the field of PAH is the heterogeneity of clinical presenations and clinical outcomes. The common denominator is increased pulmonary artery pressure and pulmonary vascular resistantce So what I want to do over the next 45 minutes is go through a couple of our cases, I will be welcoming of your insight and input on these cases. Then I will detail some of the challenges with the data surrounding these cases. I think we have some solutions for these cases through novel clinical trial designs. And then we can touch on future directions. OUTLINE: Cases Challenges with PAH trials Novel trials Future directions.
Objectives• Describe the clinical presentation and diagnosis of PH,
including interpretation of ECG, CXR and related labs.
• Develop appropriate treatment strategies using the Dana Point classification system and the modified NYHA classification of functional status.
• Compare the mechanisms of pathogenesis associated with the development of pulmonary hypertension and CorPulmonale.
• Describe the clinical course and potential complications associated with pulmonary hypertension.
Pulmonary Hypertension Lessons1. Pulmonary Hypertension (PH) is common and serious.
2. Know the Pulmonary Arterial Hypertension (PAH) clinical clues.
3. Always Look for the Underlying Cause of PH:- Definitive Diagnosis of PAH Requires Invasive
Hemodynamic Testing.
4. Treatment of PH:- Get the Diagnosis Correct and Determine Functional
Status.
Pulmonary Hypertension is common and serious.
Definition of Pulmonary Hypertension
PH
PAHMean PAP ≥ 25 mm Hg plusPCWP ≤15 mm Hg plusPVR >3 Wood units
Mean PAP ≥ 25 mm Hg at rest during cardiac catheterization
The hemodynamic working definition of PAH listed here is derived from the 2013 Proceedings of the 5th World Symposium on PH. It describes a subpopulation of patients with PH characterized by the presence of precapillary PH, including an end-expiratory PAWP ≤15 mm Hg In the new recommendations, the PVR criterion of >3 Wood units has been added back in; however, there is still insufficient evidence to add an exercise criterion to this definition. RHC remains essential for a diagnosis of PH or PAH. LVEDP = left ventricular end-diastolic pressure PAH = pulmonary arterial hypertension PAP = pulmonary arterial pressure PAWP = pulmonary arterial wedge pressure PH = pulmonary hypertension PVR = pulmonary vascular resistance RHC = right heart catheterization Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50.
The clinical classification of pulmonary hypertension was updated a few years ago at the 5th World Symposium. 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), and persistent pulmonary hypertension of the newborn (PPHN) is also distinguished as Group 1 double-prime. Of note, left heart disease (Category 2) probably represents the most frequent cause of PH. Therefore, it is critically important in the diagnostic workup to distinguish right heart from 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. CHD = congenital heart disease COPD = chronic obstructive pulmonary disease CTEPH = chronic thromboembolic pulmonary hypertension HIV = human immunodeficiency virus ILD = interstitial lung disease PCH = pulmonary capillary hemangiomatosis PVOD = pulmonary veno-occlusive disease Simonneau G et al. J Am Coll Cardiol. 62:D34-D41.
Epidemiology of PH by Echo
Miscellaneous, 2.7%
Lung disease,Sleep-related
hypoventilation,9.3%
CTEPH, 2.0%
PAH, 2.7% Unknown,
15.4%
Left heartdisease, 67.9%
N=936 of 10,314 patients with echo PASP >40 mm Hg.Strange G et al. Heart. 2012;98:1805-1811.
Presenter
Presentation Notes
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 in 936 patients found to have PH on echo. Not unexpectedly, the majority had left heart disease and, importantly, only a small number (2.7%) 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 Single echo lab / Australian community of 165,450. Etiology of PH noted on echocardiogram. Strange G et al. Heart. 2012;98:1805-1811.
Pulmonary Hypertension Is Common in Elderly Patients With Diastolic Heart Failure
Lam CS et al. J Am Coll Cardiol. 2009
100
75
50
25
0
PH p
reva
lenc
e (%
)
HTN
8
Diastolic HF
83
p<0.001
Presenter
Presentation Notes
PH is quite common in elderly patients with diastolic heart failure (HF; or, HF with preserved ejection fraction [HFpEF]) and can be severe. Lam et al, in this community-based study of 244 HFpEF patients (age 76±13 years; 45% male), found that PH was present in 83%. PASP increased with PCWP (r =0.21; p<0.007). Adjusting for PCWP, PASP was higher in HFpEF than HTN (p<0.001). The risk for PH rose substantially with documented diastolic HF. Control subjects were 719 adults with HTN without HF (age 66±10 years; 44% male). HF was defined at a somewhat low pressure (RVSP >35 mm Hg), particularly given the age range. Nevertheless, the median in the HF group was an RVSP of 48 mm Hg, and 25% had an RVSP of 56 mm Hg or higher. This should make us think first of diastolic HF in older persons presenting with dyspnea on exertion/PH. Other causes of PH, such as chronic lung disease, OSA, or chronic thromboembolic disease, should also be considered in patients with PH. Patients with PH: Older. higher systolic BP. larger LA size. higher E/e’ ratio. Lam CS. J Am Coll Cardiol. 2009;53:1119.
Maron BA et al. Circulation. 2016
Increased Pulmonary Artery Pressure is associated with increased Mortality
Presenter
Presentation Notes
The adjusted hazard ratio for mortality according to mean pulmonary artery pressure (mPAP). The hazard ratio (95% confidence interval) for all-cause mortality is plotted for mPAP between 11 and 60 mm Hg relative to a reference value of 10 mm Hg.
Prognosis is worst in PH from Lung Disease
Gall et al. JHLT. 2017
Know the PAH clinical clues.
Is There a Reason to Suspect PAH?Clinical Presentation
REVEAL. Brown LM et al. Chest. 2011;140:19-26. Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Presenter
Presentation Notes
This slide lists common initial symptoms and clinical presentation that give cause to suspect PAH. Special attention should be given to: Dyspnea, when it behaves in a relentless and progressive fashion over a period of months to a couple of years, as compared with “dyspnea” that waxes and wanes from week to week or varies according to the season (eg, entities such as asthma are more likely to explain variable dyspnea). Syncope, when it is exercise- or activity-related. Patients who feel like “passing out” after going up a flight of stairs are more likely to have limited CO and brain perfusion (caused by severe PAH and other serious entities) as compared with people who feel they might pass out while sitting down watching TV or when they turn their heads too fast. The latter more likely reflects some other types of vertigo/dizziness less likely related to decreased brain blood flow because of cardiac issues. JVD = jugular venous distention RV = right ventricular REVEAL. Brown LM et al. Chest. 2011;140:19-26. Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619
Risk factors that also increase suspicion of PAH are listed here. Notably, approximately 10% of patients with idiopathic PAH will have a familial component. Connective tissue disease—especially systemic scleroderma (SSc)—is a major risk factor for PAH, as is congenital heart disease (CHD). Patients with portal hypertension—orthotopic liver transplant candidates—are at higher risk as well. Environmental/drug factors: typically associated with anorexigen use in the 1990s was found to lead to a higher risk of PAH (very similar clinically and histopathologically to idiopathic PAH). Current data suggest that other agents such as methamphetamines could have a similar association and increase the risk of developing pulmonary arterial disease. Odds ratio for risk of developing idiopathic PAH was 7.5 for patients who used anorexigens for >6 months (95%CI, 1.7-32.4) McGoon M et al. CHEST. 2004; 126:14S–34S. Rich S et al. CHEST. 2000; 117:870–874. Chin KM et al. CHEST. 2006 Dec;130:1657-63.
Right Axis RVH
Right Atrial Enlarge-ment
RV Strain
Is There a Reason to Suspect PAH?
ECG
Presenter
Presentation Notes
Lack of right heart strain findings in a patient with “significant” or “severe” PH by echo should raise suspicion for causes of PH other than PAH, such as left heart disease (LHD) in the form of non-systolic heart failure (diastolic dysfunction). Presence of significant LV hypertrophy, left atrial enlargement, left axis deviation, or atrial fibrillation might suggest underlying left heart disease as the cause of the patient’s PH (pulmonary venous hypertension).
Normal
Abnormal
RV enlargement into retrosternal clear space
Peripheral hypo-vascularity (pruning)
Prominent centralpulmonary artery
Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Is There a Reason to Suspect PAH?
CXR
Presenter
Presentation Notes
While the chest x-ray findings shown here can be very specific for the presence of elevated PAP and right-heart strain, these are typically late findings. It is not unusual to have a normal or “unremarkable” chest x-ray in early stages of PAH. A normal x-ray should not rule out the presence of PH.
Substrate Further Assessment Rationale
Known BMPR2 mutation
Echo yearly; RHC if echo shows evidence of PAH
Early PAH detection; 20% chance of developing PAH
Systemic sclerosis*
Echo yearly; RHC if echo shows evidence of PAH 8% prevalence of PAH
HIV Echo if symptomatic; RHC if echo shows evidence of PAH 0.5% prevalence of PAH
Portal hypertension
Echo if OLT considered; RHC if echo shows evidence of PAH
4% prevalence of PAH; predictive of poor outcome
Congenital heart disease
Echo and RHC at diagnosis; consider repair of L-R shunt defect
High PAH probability if unrepaired (Eisenmenger)
Screening Guidelines: Patients With Known PAH Risk
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Presenter
Presentation Notes
The ACCF/AHA guidelines offer a roadmap for screening and further assessment, based on substrate in associated PAH. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Diagnostic Algorithm for PH• Identical for local practitioners and PH specialists• Requirements:
– thorough evaluation– high quality studies and interpretation
• Establish a suspicion of PAH
• Confirm the diagnosis (right heart catheterization)
• Classify the type of PH (Group I-V)
• Determine the disease severity
• Select the appropriate treatment for patients with PAH
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Presenter
Presentation Notes
The sequence is the same for local practitioners and PH specialists: Establish a suspicion of PAH Confirm the diagnosis (right heart catheterization) Classify the type of PH (Group I-V) Determine the disease severity Select the appropriate treatment for patients with PAH McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619
• “echocardiographic findings suggestive of PH should prompt referral to specialized centers for further evaluation to appropriately diagnose the etiology of the PH and classify them in to one or more of the clinical classification groups.”
Thenappan et al. (Under review).
Definitive Diagnosis of PAH Requires Invasive Hemodynamic Testing.
Right Heart CatheterizationFor reference
PAVC RA RV PVPC
LA LV Ao
Pulmonary venous hypertensionElevated PCWP, normal PVR
PAHPH with respiratory diseaseCTEPHNormal PCWP, elevated PVR
PH: mean PA pressure > 25 mmHg at rest during cardiac catheterization
Post-capillary PH PCWP >15 mm Hg
PVR <3 Wood units
Pre-capillary PHPCWP <15 mm HgPVR ≥3 Wood units
For reference
Presenter
Presentation Notes
Right heart catheterization (RHC) is the diagnostic gold standard for PH. It is an extremely important step—without it one cannot diagnose 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 slide represents the cardiovascular connections in series: [VC=vena cava, RA=right atrium, RV=right ventricle, PA=pulmonary artery, PC=pulmonary capillary bed, PV=pulmonary venous bed, LA=left atrium, LV=left ventricle, Ao=aorta]. Patients with PH in WHO group I (PAH), III, or IV have “pre-capillary” PH, where the left-sided filling pressure (PWCP and/or LVEDP) is normal and the pulmonary vascular resistance (PVR) is elevated. In the case of pulmonary venous hypertension (aka “passive” or “post-capillary” PH), which is related to diseases of the left heart, PA mean pressure and PCWP are elevated, whereas PVR is normal. For some patients the picture is mixed: left-sided filling pressure and PVR are both elevated. Clinically, this situation is seen most commonly with advanced systolic LV failure or restrictive cardiomyopathy (typically associated with “reactive” pulmonary vasoconstriction). Patients with a high CO state (“hyperkinetic” PH) have elevated mean PAP and CO, yet normal LV filling pressure and PVR.
Treatment of PH—Get the Diagnosis Correct and Determine
Functional Status.
Group 2 PH
PH secondary to Left-sided Heart Disease
Is It Left Heart Disease?Symptoms
– paroxysmal nocturnal dyspnea
– orthopnea
History– diabetes
– hypertension
– obesity
– coronary artery disease
– metabolic syndrome
ECG– atrial fibrillation
– absence of right axis deviation
Echo– left atrial enlargement
– left ventricular hypertrophy
– normal RA, RV
– abnormal diastolic filling
Presenter
Presentation Notes
Though certainly not exclusive of PAH, the presence of conditions on this slide is more suggestive of left heart disease. ECG = electrocardiogram RA= right atrium RV = right ventricle
• Is potentially curable with pulmonary endarterectomy (PEA).
• 3% to 4% of acute PE do not entirely resolve.
• One half of those with CTEPH do not have an apparent history of acute PE.
• Normal VQ scan excludes chronic PE.
• CT angiogram can detect chronic clot.
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
For reference
Presenter
Presentation Notes
An evaluation for chronic thromboembolic disease is an essential component of the diagnostic workup of PAH. Even if your suspicion of chronic thromboembolic pulmonary hypertension (CTEPH) is low, a VQ scan, CT pulmonary angiography, or pulmonary angiogram needs to be performed.
Group 1 PH
Pulmonary Arterial Hypertension (PAH)
Schematic Progression of PAH
Time
PAP
PVR
Presymptomatic/ Compensated
Symptomatic/ Decompensating
Symptom Threshold
Right Heart Dysfunction
Declining/ Decompensated
CO= TPGPVR
TPG=transpulmonary gradient.
Presenter
Presentation Notes
This slide represents a synthesis of human and animal models of PAH that shows a putative model of disease progression. Pulmonary hypertension may be classified into 3 rough categories, pre-symptomatic/compensating, symptomatic/decompensating, and declining/decompensated. In this hypothetical model, as the vascular pathology progresses (proliferation of intima, hyperplasia of the SMC, and adventitial fibrosis), PVR increases and pulmonary artery pressure rises in concert in order to maintain CO. As long as the RV is able to compensate for the resistance, pressure continues to increase as PVR increases. The increased RV workload causes the RV to hypertrophy and its efficiency falls, right heart failure ensues, and PAP will fall as the patient decompensates. Failure to maintain CO leads to the symptoms of the disease and ultimately right heart dysfunction and death. CO = Cardiac Output PAP = Pulmonary arterial pressure PVR = Pulmonary vascular resistance
Mechanisms of Action of Approved Therapies for PAH
Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.
cGMPcAMP
Vasoconstriction and proliferation
Endothelinreceptor A
Endothelin-receptor
antagonists
Endothelinreceptor B
Phosphodiesterase type 5 inhibitor
Vasodilationand antiproliferation
Phosphodiesterase type 5
Vasodilationand antiproliferation
Prostacyclin derivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric OxidePathway
EndothelinPathway
ProstacyclinPathway
Endothelial cellsProendothelin
Endothelial cellsArachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
Exogenous nitric oxide sGCstimulator
For reference
Presenter
Presentation Notes
FOUR major categories of therapy are now approved for treatment of PAH. These therapies target endothelial cell dysregulation and smooth muscle cell tone and proliferation. Three major pathways are involved: The endothelin pathway The nitric oxide pathway, including PDE-5 inhibitors that enhance NO-mediated vasodilation; AND an sGC stimulator agent that interacts synergistically with available NO to stimulate guanylate cyclase, leading to increased cGMP production The prostacyclin pathway
PAH Treatment Goals
• Improve survival.
• Improve quality of life.
• Improve exercise capacity. – 6MWD– WHO functional
Key PAH treatment goals are listed on this slide. Ideally, we attempt to meet all of these goals with each patient, but that is not always possible. Each PAH case is different and patient response to treatment is variable, so clinicians need to monitor and reevaluate the patient’s condition, working toward meeting these goals. When these goals are met, patients can perform activities of daily living well enough to experience and participate in those things that are important for their own happiness and peace of mind. Our success attaining these goals depends on several factors: severity of PAH disease optimal therapy response to therapy compliance
Initial Therapy: Making the Right Decision
• Make sure the patient truly has PAH.
• Severity of disease.
• Patient preference.
• Trying to weigh the data (evidence-based).
Presenter
Presentation Notes
Making the right decision for initial treatment requires weighing: Severity of disease Patient preference Clinical data Objective assessment of baseline characteristics, such as 6MWD and hemodynamics
Chronic Adjuvant Treatment
• Use to prevent hypoxic vasoconstriction.
• Consider exercise, sleep, altitude.
• Aim for target saturation >90%.
• May not correct hypoxia with shunt.
Oxygen
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Diuretics• Most patients need diuretics.
• Renal function and electrolytes must be monitored closely.
Presenter
Presentation Notes
Adjuvant therapies that might be employed chronically include anticoagulation ± diuretics ± oxygen ± digoxin. This slide summarizes key points about diuretics and oxygen. Digoxin has a variable inotropic effect and use, and in the absence of long-term data, clinicians must balance unproven benefits with known risks. Oxygen is used to prevent hypoxic vasoconstriction. It requires baseline testing to evaluate ability to maintain oxygen levels with sleep (overnight oximetry), activity (6MWT), as well as rest. The aim is saturation of >90%. Oxygen may not correct hypoxia with a shunt.
(+) Vasodilator Response
(−) Vasodilator Response or Non-sustained Vasodilator Response
PAH Therapy
• Calcium channel blockers
• Endothelin receptor antagonists• Phosphodiesterase-5 inhibitors• sGC stimulator• ProstanoidsMcLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
Presenter
Presentation Notes
The starting point in determining the initial treatment in many patients is the result of acute vasoreactivity testing. Patients demonstrating acute significant vasoreactivity under hemodynamic monitoring may benefit from an extremely simple and inexpensive therapy (CCBs) and have an excellent prognosis. Indeed, survival of those patients appropriately treated with CCBs is nearly normal, compared with patients who do not demonstrate acute vasoreactivity, or a sustained clinical response to CCBs despite initial acute vasoreactivity. Unfortunately, few patients (thought to be approximately 10%) are true acute vasoresponders, and of these only about half will demonstrate a sustained clinical improvement with CCB therapy. If CCB therapy is cheap and effective, why not just try everyone on it at first and avoid the cath in some patients? The reason is that empirical trials of CCBs in patients with PH, and particularly with cor pulmonale, can be extremely dangerous. We are hoping (if we do this empirically) that the beneficial effects of pulmonary vasodilation to promote increased RV function will outweigh the very likely negative inotropic effects and systemic hypotensive effects in patients who already have decreased RV function and, frequently, low systemic blood pressures. The net response is highly variable, influenced by the disease and drugs used; and the risks, if there is not significant pulmonary vasodilatory response, are significant, including syncope and death. Thus, CCBs must NOT be used without initially demonstrating that pts have a true acute vasoreactivity to a short-acting vasodilator (adenosine, NO, IV epo) in the cath lab 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. The majority of patients with PAH have a negative response to acute vasoreactive testing. These patients most likely will receive treatment with an ERA, PDE-5 inhibitor, sGC stimulator, and/or a prostanoid.
Acute Vasodilator Trial• Purpose:
– identify vasodilator “responders” who are candidates for CCB therapy
• Short-acting vasodilators– inhaled nitric oxide is preferred
• Definition of response– decrease in mPAP by ≥10 mm Hg down to
mPAP of ≤40 mm Hg– with improvement or maintenance of
cardiac output
Rubin LJ. Chest. 2004;126:4S-6S.
For reference
Presenter
Presentation Notes
Rubin and colleagues conducted an acute (short-acting) vasodilator trial to identify vasodilator “responders” who are candidates for CCB therapy. They defined response as a decrease in mPAP by ≥10 mm Hg down to mPAP of ≤40 mm Hg, with improvement or maintenance of cardiac output. Rubin LJ. Chest. 2004;126:4S-6.
Sample Acute Vasodilator Responses
PATIENT A PATIENT BBASELINE AFTER 40 PPM iNO BASELINE AFTER 40 PPM iNO
mPAP 45 mm Hg mPAP 34 mm Hg mPAP 45 mm Hg mPAP 37 mm Hg
PCWP 10 mm Hg PCWP 10 mm Hg PCWP 10 mm Hg PCWP 7 mm Hg
CO 5 L/min CO 6 L/min CO 5 L/min CO 6 L/min
PVR 7 Wood units PVR 4 Wood units PVR 7 Wood units PVR 5 Wood units
RESPONDER OR NON-RESPONDER??
RESPONDER OR NON-RESPONDER??
For reference
Presenter
Presentation Notes
Speaker: Read the conditions for each patient pre- and post-40 ppm iNO. Is Patient A a responder? Is Patient B a responder? Speaker: Go through each case and define why Patient A is a responder, but Patient B is not.
Sample Acute Vasodilator ResponsesPATIENT A PATIENT B
BASELINE AFTER 40 PPM iNO BASELINE AFTER 40 PPM iNO
mPAP 45 mm Hg mPAP 34 mm Hg mPAP 45 mm Hg mPAP 37 mm Hg
PCWP 10 mm Hg PCWP 10 mm Hg PCWP 10 mm Hg PCWP 7 mm Hg
CO 5 L/min CO 6 L/min CO 5 L/min CO 6 L/min
PVR 7 Wood units PVR 4 Wood units PVR 7 Wood units PVR 5 Wood units
RESPONDER: TREAT WITH CALCIUM CHANNEL BLOCKER
NON-RESPONDER: STILL TREATABLE, BUT NOT WITH
CALCIUM CHANNEL BLOCKER
For reference
Presenter
Presentation Notes
Emphasize the point that Patient A is a responder, and should be treated with a CCB. Patient B is a non-responder BUT can still be treated. No response to acute vasodilator challenge means no CCB, but still means that the patient can and should be treated with selective pulmonary vasodilators if documented PAH is present.
PAH Determinants of Risk
McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
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
Presenter
Presentation Notes
It is helpful, in determining the optimal treatment for patients with a negative response to acute vasoreactive testing, to consider whether the patient is at lower or higher risk. This table categorizes determinants of risk, including clinical evidence of RV failure disease progression (gradual vs rapid) WHO functional class (II or III vs IV) 6-minute walk distance (6MWD; longer [>400 m] vs shorter [<300 m]) BNP (minimally vs markedly elevated) echo findings (minimal RV dysfunction vs significant RV enlargement/dysfunction, pericardial effusion) hemodynamics (normal/near normal RAP, CI vs high RAP, low CI) BNP = brain natriuretic peptide CI = cardiac index CPET = cardiopulmonary exercise test 6MWD = 6-minute walk distance RA = right atrium RAP = right atrial pressure RV = right ventricle WHO = World Health Organization McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.
WHO functional class: modified NYHA classification of functional status
NYHA Functional ClassI. No limitation of physical
activity. Ordinary physical activity does not cause shortness of breath (SOB).
II. Slight limitation of physical activity. Ordinary physical activity results in SOB.
III. Marked limitation of physical activity. Less than ordinary activity causes SOB.
IV. SOB at rest.
WHO Functional ClassI. No limitation of physical
activity. Ordinary physical activity does not cause shortness of breath (SOB).
II. Slight limitation of physical activity. Ordinary physical activity results in SOB.
III. Marked limitation of physical activity. Less than ordinary activity causes SOB.
IV. SOB at rest or syncope.
Presenter
Presentation Notes
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath).
• Supervised exercise training (I-A)• Psycho-social support (I-C)• Avoid strenuous physical activity (I-C)• Avoid pregnancy (I-C)• Influenza and pneumococcal
immunization (I-C)
• Oral anticoagulants: – IPAH, heritable PAH, and PAH
due to anorexigens (IIa-C)– APAH (Ilb-C)
• Diuretics (I-C)• Oxygen (I-C)• Digoxin (IIb-C)
Continue CCB
WHO FC I-III CCB (I-C)
Sustained response(WHO FC I-II)
VASOREACTIVE NON-VASOREACTIVE
5th World Symposium on PH:2013 PAH Treatment Algorithm
Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.
INITIAL THERAPY WITH PAH-APPROVED DRUGS
YES
NO
Acute vasoreactivity test (I-C for IPAH) (IIb-C for APAH)
Expert Referral (I-C)
General measures and supportive therapy
Presenter
Presentation Notes
What is the optimal treatment strategy? This slide depicts the most recently released evidence-based treatment algorithm for treatment of PAH, as formulated at the 5th World Symposium on PH in 2013, leading up to initiation of PAH-approved therapy. The suggested initial approach after the diagnosis of PAH is the adoption of the general measures, the initiation of the supportive therapy, and referral to an expert center. APAH = associated pulmonary arterial hypertension CCB = calcium channel blockers IPAH = idiopathic pulmonary arterial hypertension PAH = pulmonary arterial hypertension WHO FC = World Health Organization functional class Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.
5th World Symposium on PH:2013 Treatment Algorithm
Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.
Sequential CombinationTherapy (I-A)
Referral for LungTransplantation (I-C)
Consider Eligibility for Lung Transplantation
Inadequate ClinicalResponse
on Maximal Therapy
INITIAL THERAPY WITH PAH-APPROVED DRUGS
PDE-5 I orsGCs
ERAs
Prostanoids
++
+
Balloon AtrialSeptostomy (IIa-C)
Inadequate ClinicalResponse
Presenter
Presentation Notes
After initial therapy, the next steps are based on the clinical response, which is usually reassessed at 3 to 6 months after treatment start. The clinical response is based on the evaluation of different parameters, including WHO FC, exercise capacity, cardiac index, right atrial pressure, NT-proBNP plasma levels, echocardiographic parameters, and perceived need for additional/change of therapy. The patterns to apply combination therapy may be sequential or initial (upfront). Sequential combination therapy is the most widely utilized strategy both in RCTs (12 of 13 of the RCTs with combination therapy) The rationale for initial or upfront combination therapy is based on the known mortality of PAH that is reminiscent of many malignancies and the fact that malignancies and critical medical illnesses (heart failure, malignant hypertension) are not treated with a stepwise approach to therapy but rather with preemptive combination therapy. FC = functional class NT-proBNP = N-terminal pro-brain natriuretic peptide PAH = pulmonary arterial hypertension PDE-5 = phosphodiesterase enzyme, subtype 5 PH = pulmonary hypertension RCT = randomized controlled trial SGC = soluble guanylate cyclase WHO = World Health Organization Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.
Prognosis improves with PAH-therapies
Humbert M et al. Circulation. 2010;122:156-163.
0 12 24 36Time (mo)
Survival (%)
0
40
80
100
60
20
Observed
Predicted (NIH Registry)
No. at risk:All patients 56 98 120 13369 113 127
Presenter
Presentation Notes
Data from the French Registry corroborate these findings. This slide shows the Kaplan-Meier survival estimates in the combined population of patients with PAH. Using the predictive modeling approach of the NIH Registry, the estimated survival (grey line) was about 10% lower than what was actually observed. Registry Background and More Specific Findings: The French Registry prospectively enrolled 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated PAH (56 incident and 298 prevalent cases) between October 2002 and October 2003. Patients were followed for 3 years and survival rates analyzed. Patients were treated with targeted therapies such as prostacyclin derivatives, ERAs, and PDE-5 inhibitors according to usual practice at each center. For incident cases, estimated survival (95% CI) at 1, 2, and 3 years was 85.7% (76.5–94.9%), 69.6% (57.6–81.6%), and 54.9% (41.8–68.0%), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years prior to study entry; n=190), 1-, 2-, and 3-year survival estimates were 82.9% (72.4–95.0%), 67.1% (57.1–78.8%), and 58.2% (49.0– 69.3%), respectively. Multivariate analysis revealed that female gender, a greater 6MWD, and higher CO were jointly significantly associated with improved survival. An individual survival analysis identified being female, NYHA functional class I/II, greater 6MWD, lower RAP, and higher CO as significantly and positively associated with survival. Mortality was most closely associated with male gender, RV hemodynamic function, and exercise limitation. 6MWD = 6-minute walk distance CI = cardiac index CO = cardiac output ERA=endothelin-receptor antagonists NIH = National Institutes of Health NYHA = New York Heart Association PAH = pulmonary arterial hypertension PDE-5 = phosphodiesterase enzyme, subtype 5 RAP = right atrial pressure RV = right ventricle (ventricular) Humbert M et al. Circulation. 2010;122:156-163.
Summary1. PH is common and serious.
2. Know the PAH clinical clues.
3. Always Look for the Underlying Cause of PH:- Definitive Diagnosis of PAH Requires Invasive
Hemodynamic Testing.
4. Treatment of PH:- Get the Diagnosis Correct and Determine Functional
Status.
Objectives• Describe the clinical presentation and diagnosis of PAH,
including interpretation of ECG, CXR and related labs.
• Develop appropriate treatment strategies using the Dana Point classification system and the modified NYHA classification of functional status.
• Compare the mechanisms of pathogenesis associated with the development of pulmonary hypertension and CorPulmonale.
• Describe the clinical course and potential complications associated with pulmonary hypertension.
"We don't do it for the glory. We don't do it for the recognition... We do it because it needs to be done. Because if we don't, no one else will. And we do it even if no one knows what we've done.”
