for Specialists

1. HOW DO I DIAGNOSE PAH EARLY?

1HOW DO I DIAGNOSE PAH EARLY?

What Can Be Done To Clinically Diagnose Pulmonary Arterial Hypertension Early?

Pulmonary arterial hypertension (PAH) is slow to diagnose because the symptoms of the disease mimic those of more common diseases and may be mild to nonexistent in the early stages of the disease.1,2,3

  • Since the symptoms may be common, patients may fail to seek medical attention or physicians may delay pursuing diagnosis4
  • Other tests can be used to help in aiding the early diagnosis of PAH5
  • While several tests help to diagnose PAH and rule out other diseases, right heart catheterization (RHC) is the only definitive test to confirm PAH5,6

Clinical Presentation6

  • Syncope
  • Angina
  • Dyspnea
  • Edema

Potential Causes

  • Hemodynamic: Systemic vasodilation (exertion, orthostatic, vasodepressor) and low-fixed cardiac output (CO) due to high pulmonary resistance
  • Arrhythmic: Benign arrhythmias (atrial fibrillation) result in loss of atrial contribution to CO; Malignant arrhythmias provoked by wall stretch, ischemia
  • Many symptoms are non-descript7
  • Consistent monitoring of potential causes of symptoms that mimic those of more common disease could contribute to earlier diagnosis of PAH2,3,7

Referring Patients With Suspected PAH

Clinical suspicion of PAH should arise in any case of breathlessness without overt signs of specific heart or lung disease.8

  • The same can be applied in patients with underlying lung or heart disease whenever there is an increase in dyspnea unexplained by the underlying diseases itself8
  • The combination of worsening dyspnea, chest pain on exertion, and syncope or near syncope, likely represents advanced disease and to refer these patients to a PAH center must become second nature for clinicians9

Algorithm for Evaluation of Suspected PAH8*

*Algorithm is from the 2004 ESC/ERS Guidelines Algorithm for Evaluation of Suspected PAH.

ABG=arterial blood gases; Cath=catheterization; CT=computerized tomography; ECG=electrocardiogram; PH=pulmonary hypertension; TT=transthoracic; VO2=oxygen consumption.

  • After suspicion of pulmonary hypertension (PH) due to symptoms and findings from physical examination and screening procedures, detection of PH is to be done by ECG, chest radiograph, and TT echocardiography (TTE)8
  • The next step after detection is the identification of Clinical Class by tests such as TTE, pulmonary function tests, and ventilation/perfusion lung scan8
  • Once the clinical class of PAH has been determined, additional investigation may be required for the assessment of exercise capacity and hemodynamics by the 6-minute walk test (6MWT) and RHC, respectively8
  • RHC is required to confirm the diagnosis of PAH7

Diagnosis

PAH is a diagnosis of exclusion; therefore, multiple tests may be required to assess the probability of this disease.10

  • According to the 2015 European Society of Cardiology/European Respiratory Association (ESC/ERS) Guidelines, echocardiography should always be performed when PH is suspected and may be used to infer a diagnosis of PH in patients with multiple different echocardiographic measurements consistent with this diagnosis7

Echocardiographic Probability of PH in Symptomatic Patients7

  • The probability of PH is based on the peak tricuspid regurgitation velocity (TRV) at rest and on the presence of additional pre-specified echocardiographic variables (PH Signs in above table)7
  • The probability is then measured as low, intermediate, or high7
  • When interpreted in a clinical context, the echocardiographic result is required to decide the need for RHC in individual patients7

Additional Echocardiographic Signs Suggesting PH7*

PA=pulmonary artery.

*In addition to tricuspid regurgitation velocity measurement in the table above.

†Echocardiographic signs from at least 2 different categories (A/B/C) from the list should be present to alter the level of echocardiographic probability of PH.

In order to facilitate and standardize the assessment of the level of probability of PH, several echocardiographic signs are proposed in addition to the criteria based on TRV.7

  • The recommended plan for further patient investigation is based on echocardiographic probability of PH in symptomatic patients shown below7

Suggested Diagnostic Management According to Echocardiographic Probability of PH7*

CTEPH=chronic thromboembolic pulmonary hypertension; Echo=echocardiographic; RHC=right heart catheterization.

*In patients with symptoms compatible with PH, with or without risk factors for pulmonary arterial hypertension or chronic thromboembolic PH.

†These recommendations do not apply to patients with diffuse parenchymal lung disease or left heart disease.

‡Class of recommendation.

§Level of evidence.

ǁDepending on the presence of risk factors for PH group 2, 3, or 5.

Additional Tests

Tests within the physical examination and laboratory test results can aid in the early diagnosis of PAH.

  • Physical Examination can reveal cardiovascular findings11
  • Laboratory tests can aid in the early diagnosis of PAH7,12
  • Jugular venous pressure
  • Hepatomegaly
  • Ascites
  • Accentuated P2 sounds
  • Elevated resting heart rate
  • Low blood pressure
  • Lower-extremity edema

The Role of RHC in the Diagnosis of PAH

RHC is the only definitive procedure to confirm PAH and is recommended for all adult patients with suspected PAH.7,13

  • The findings help distinguish PAH from pulmonary venous hypertension (PVH)14
  • They also help clarify the amount of hemodynamic impairment and to test the vasoreactivity of the pulmonary circulation8
  • Thus, appropriate PAH management options can be applied once disease severity has been established14

RHC Measures that Confirm a Diagnosis of PAH14*:

The formal diagnosis of PAH is based on the following results from the RHC test:

  • 1

    Elevated mean pulmonary arterial pressure (mPAP): ≥ 25 mm Hg

  • 2

    Normal pulmonary artery wedge pressure (PAWP): ≤15 mm Hg

  • 3

    Elevated pulmonary vascular resistance (PVR): >3 Wood Units (WU)

*All values are measured at rest.

2 WHY IS EARLY DIAGNOSIS KEY?

Early Diagnosis is Key in Pulmonary Arterial Hypertension Management

PAH is a progressive, potentially life-threatening disease that affects the lungs and subsequently the heart.5,15

  • Historically, the majority of undiagnosed and untreated patients progress to the New York Heart Association functional class (NYHA FC) III before they are diagnosed with advanced abnormalities that are detected by physical examination, laboratory tests, or hemodynamic assessments of the pulmonary circulation4*
  • Despite the availability of multiple treatments, mortality after 5 years remains high in newly and previously diagnosed patients who are classified as NYHA FC III16 (see figure below for previously diagnosed patients)
  • There is often a delay of approximately 2.8 years from symptom onset to a formal diagnosis17

5-Year Survival Rate in Previously Diagnosed NYHA FC III Patients at Enrollment in the REVEAL Registry16†

*Data are from the Patient Registry for the Characterization of Primary Pulmonary Hypertension, initiated by the National Institute of Health in 1981. This multicenter, prospective registry included 32 medical centers in the United States with 187 patients with primary pulmonary hypertension enrolled from July 1981 to September 1985. Limitations include lack of standardized follow-up assessments; prospective studies are needed to validate findings.


†Data are from the Registry to Evaluate Early and Long-term PAH disease management (REVEAL Registry), a large, multicenter, prospective cohort registry that included 54 centers in the United States. 2,967 patients were enrolled between March 2006 and September 2007, all with newly or previously diagnosed World Health Organization group I PAH and pre-specified hemodynamic criteria by right-heart catheterization test. Limitations include lack of standardized follow-up assessments; prospective studies are needed to validate findings.

The Negative Impact of Delayed Diagnosis and Treatment

The REVEAL registry data showed that the mean time of symptom onset to formal diagnosis was ~2.8 years.17

REVEAL Registry*

In patients who died of PAH-related causes (N=487) ~35% were on monotherapy or no treatment at the time of death18

*Data are from the Registry to Evaluate Early and Long-term PAH disease management (REVEAL Registry), a large, multicenter, prospective cohort registry that included 54 centers in the United States. 2,967 patients were enrolled between March 2006 and September 2007, all with newly or previously diagnosed World Health Organization group I PAH and pre-specified hemodynamic criteria by right-heart catheterization test.

NIH Registry†

The National Institute of Health (NIH) initiated the Patient Registry for the Characterization of Primary Pulmonary Hypertension. The prospective study from the national registry data suggests that delayed diagnosis of PAH is quite common with the mean time of onset of symptoms to formal diagnosis was roughly 2 years (see the figure below).4

†Data are from the Patient Registry for the Characterization of Primary Pulmonary Hypertension, initiated by the National Institute of Health in 1981. This multicenter, prospective registry included 32 medical centers in the United States with 187 patients with primary pulmonary hypertension enrolled from July 1981 to September 1985.

Frequency of Formal Diagnosis from Symptom Onset in the NIH Registry4

The disease was most prevalent in age groups in the third and fourth decades but the female to male ratio of 1:7 to 1 was not significantly different among decades. The mean time to onset of initial symptoms to diagnosis, 2.03 years (median 1.27), was similar for both male and female patients.4

Pulmonary Hypertension Connection Registry‡

Only 58% of PAH patients with functional class I survived 5 years post-diagnosis when their PAH was managed suboptimally15 (see the figure below).

Survival Rate for Functional Class I PAH Patients in the Pulmonary Hypertension Connection Registry15

‡Data are from the Pulmonary Hypertension Connection Registry, which evaluated 1,360 patients prospectively from 1982-2004 and prospectively from 2004-2006 at a single USA practice over time at three different university hospitals (University of Illinois, Rush University Medical Center, and University of Chicago, all Chicago, IL, USA). The survival estimates are from the cohort of n=578 incident/prevalent patients. Limitations include that this was an observational study with a large number of patients entered retrospectively which can lead to lost data or inconclusive data for analysis.

How Sick Is Your PAH Patient?

It is imperative to determine the patient's functional class (FC) to help establish disease severity. The World Health Organization (WHO) classify patients according to their FC from I to IV (see table below).6

Functional Classifications6

WHO Definition

Functional Classifications

Patients with PH in whom there is no limitation of usual physical activity; ordinary physical activity does not cause increased dyspnea, fatigue, chest pain, or presyncope

I

Patients with PH who have mild limitation of physical activity. There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope

II

Patients with PH who have a marked limitation of physical activity. There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope

III

Patients with PH who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Dyspnea and/or fatigue may be present at rest, and symptoms are increased by almost any physical activity

IV

PH, pulmonary hypertension.

Importance of Functional Class Status

Evidence suggests that newly diagnosed FC III patients who improve their functional class may achieve increased survival rates (see figure below).19

Survival Rates for PAH Patients Based on Functional Class Over Time in the REVEAL Registry19*

*Data are from the Registry to Evaluate Early and Long-term PAH disease management (REVEAL Registry), a large, multicenter, prospective cohort registry that included 54 centers in the United States. 2,967 patients were enrolled between March 2006 and September 2007, all with newly or previously diagnosed World Health Organization group I PAH and pre-specified hemodynamic criteria by right-heart catheterization test.

  • The survival rate of FC III PAH patients who were able to improve their functional class was significantly increased compared to those who were unchanged or worsened over a 3-year period19

Impact of Risk Factor Severity on Long-term Survival in Newly Diagnosed PAH Patients

Patients newly diagnosed with PAH who were not able to achieve any of the 4 low-risk criteria at first re-evaluation (within 12 months of diagnosis) experienced a marked decrease in transplant-free survival over a 5-year period compared to those who achieved 2 or 4 of the criteria.20

  • The 2015 ESC/ERS PH guidelines stratifies the risk for mortality at 1 year based on clinical factors such as WHO FC, 6MWD, and hemodynamic variables7
  • The French Registry used similar clinical factors, and assessed the presence of four low-risk criteria to determine the risk for mortality at 5 years in patients newly diagnosed with PAH20
  • Patients who were unable to achieve any of the 4 low-risk criteria within the first 12-months of diagnosis had a low long-term survival rate of 34% at 5 years (see figures below)20

Low-Risk Criteria Assessed in the French Registry20*

WHO/NYHA FC6MWDRAPCl
I, II>440 m<8 mm Hg≥2.5 L/min/m2

CI=cardiac index; NYHA FC=New York Heart Association Functional Class; RAP=right atrial pressure; WHO=World Health Organization; 6MWD=6-minute walk distance.

*Data was retrospectively reviewed from the French PAH Registry, a large, multicenter registry which enrolled 1,017 patients with incident PAH in France from 2006 to 2016 to determine the association between the number of low-risk criteria achieved at 1 year of diagnosis and long-term prognosis.

These values are based on the 2015 ESC/ERS guidelines for low-risk criteria. Most of the proposed variables and cut-off values are based on expert opinion. They may provide prognostic information and may be used to guide therapeutic decisions, but application to individual patients must be done carefully.

Transplant-Free Survival Estimates at Follow-Up in the French Registry20†

†Data are point estimates taken from Kaplan–Meier curves at 1, 3, and 5 years.

‡Number of low-risk criteria present at diagnosis and at first re-evaluation.

3WHAT IS THE RISK ASSESSMENT STRATEGY?

Implementing an Effective Risk Assessment Strategy in Pulmonary Arterial Hypertension

What Is Essential for Risk Assessment in PAH?

Implementing risk assessment on a regular basis is suggested for the optimal management of patients with PAH.

  • Risk assessment in PAH allows the determination of patient prognosis and response to therapy, and can aid decision-making with respect to the need to modify treatment7
  • Multiple variables must be evaluated to determine disease severity since there is no single variable that provides both sufficient diagnostic and prognostic information (see table below)7
  • The 2015 ESC/ERS guidelines recommend addressing the following key risk assessment questions at each visit7:
    • Is there any evidence of clinical deterioration since the last assessment?
    • If so, is clinical deterioration caused by progression of PH or by a concomitant illness?
    • Is RV function stable and sufficient?
    • Is the current status compatible with a good long-term prognosis, ie, does the patient meet the low-risk criteria?

Variables and Timing for Risk Assessment in PAH7

ALAT=alanine aminotransferase; ASAT=aspartate aminotransferase; BNP=brain natriuretic peptide; CPET=cardiopulmonary exercise testing;

ECG=electrocardiogram; ERA=endothelin receptor antagonist; FC=functional class; INR=international normalized ratio; lab=laboratory assessment; NT-proBNP=N-terminal pro b-type natriuretic peptide; RHC=right heart catheterization; TSH=thyroid-stimulating hormone.

*Intervals to be adjusted according to patient needs.

†Basic lab includes blood count, INR (in patients receiving vitamin K antagonists), serum creatinine, sodium, potassium, ASAT/ALAT (in patients receiving ERAs), bilirubin, and BNP/NT-proBNP.

‡Extended lab includes TSH, troponin, uric acid, iron status (iron, ferritin, soluble transferrin receptor), and other variables according to individual patient needs.

§From arterial or arterialized capillary blood; may be replaced by peripheral oxygen saturation in stable patients or if BGA is not available.

ǁShould be considered.

Some centers perform RHCs at regular intervals during follow-up.

  • All of the variables listed do not need to be assessed at each visit; however, the basic assessment should include determination of the FC and at least one measurement of exercise capacity, eg, 6-minute walk distance (6MWD) or cardiopulmonary exercise testing (CPET)7
  • It is also recommended to obtain some information on RV function, either by measuring brain natriuretic peptide/N-terminal pro b-type natriuretic peptide (BNP/NT-proBNP) or by performing echocardiography7

Low-Risk as a Goal of Treatment in PAH

The 2015 ESC/ERS Guidelines recommend an overall treatment goal in PAH patients to achieve a low-risk status.7

  • In general, this means keeping or bringing the patient to WHO-FC II with an evidence-based treatment regimen7
  • Low-risk status is typically associated with better patient outcomes7
  • Low-risk status may not always be realistic and may not be achievable in patients with advanced disease, patients with severe co-morbidities, or very elderly patients7
  • Achieving or maintaining intermediate-risk status should be considered an inadequate response for most patients7

What Variables Define Low-Risk in PAH?

The 2015 ESC/ERS guidelines recommend risk assessment for patients using a multidimensional stratification according to clinical, echocardiographic, exercise, and hemodynamic variables with known prognostic significance.7,20,21

  • Based on this assessment patients can be classified as low-risk, intermediate-risk, or high-risk for clinical worsening or death7

2015 ESC/ERS Risk Assessment in PAH7

Determinants of Prognosis*
(Estimated 1-Year Mortality)
Clinical signs of right heart failure
Progression of symptoms
Syncope
Cardiopulmonary exercise testing
WHO FC
6MWD
NT-proBNP plasma levels
Hemodynamics
Imaging (echocardiography, CMR imaging)
Low Risk
(< 5%)
Absent
No
No
Peak VO2
>15 mL/min/kg
(>65% predicted)
EqCO2 slope <36
I, II
>440m
NT-proBNP
<300 ng/L
BNP <50 ng/L
RAP <8 mm Hg
CI ≥2.5 L/min/m2
SvO2 >65%
RA area <18 cm2
No pericardial effusion
Intermediate Risk
(5%-10%)
Absent
Slow
Occasional syncope†
Peak VO2
11-15 mL/min/kg
(35%-65% predicted)
EqCO2 slope 36-44.9
III
165-440m
NT-proBNP
300-1400 ng/L
BNP 50-300 ng/L
RAP 8-14 mm Hg
CI 2.0-2.4 L/min/m2
SvO2 60%-65%
RA area 18-26 cm2
No or minimal pericardial effusion
High Risk
(>10%)
Present
Rapid
Repeated syncope‡
Peak VO2
<11 mL/min/kg
(<35% predicted)
EqCO2 slope ≥45
IV
<165m
NT-proBNP
>1400 ng/L
BNP >300 ng/L
RAP >14 mm Hg
CI <2.0 L/min/m2
SvO2 <60%
RA area >26 cm2
Pericardial effusion

CI=cardiac index; CMR=cardiac magnetic resonance; CPET=cardiopulmonary exercise testing; EqCO2=ventilatory equivalent for carbon dioxide; NT- proBNP=N-Terminal pro B-Type Natriuretic Peptide; SvO2=mixed venous oxygen saturation.

*Most of the proposed variables and cut-off values are based on expert opinion. They may provide prognostic information and may be used to guide therapeutic decisions, but application to individual patients must be done carefully. One must also note that most of these variables have been validated mostly for idiopathic PAH, and the cut-off levels used above may not necessarily apply to other forms of PAH. Furthermore, the use of approved therapies and their influence on the variables should be considered in the evaluation of the risk.

†Occasional syncope during brisk or heavy exercise, or occasional orthostatic syncope in an otherwise stable patient.

‡Repeated episodes of syncope, even with little or regular physical activity.

  • The individual risk is further modified by other factors, such as the rate of disease progression and the presence or absence of signs of right heart failure, or syncope, and also by co-morbidities, age, sex, background therapy, and PAH subtype, among others7

Ensuring Utilization of the 6-Minute Walk Test

The 6MWT helps to address the severity of the disease progression as an overall indicator of functional capacity.22

  • The 6MWD is considered an important parameter for patient prognosis and determining therapeutic response
  • It measures the distance a patient can walk on a flat surface in 6 minutes and the shortness and fatigue experienced during the activity22
  • Changing the configuration of the walkway significantly affects 6MWT performance23
  • The walkway needs to be consistent every time the patient is tested to ensure that the results attained are comparable throughout time22

The 6MWT is a submaximal exercise test that serves as an indicator of the ability to perform activities of daily life.24

  • At baseline, 6MWD is generally measured at the time of diagnosis and before starting therapy; it is expected that a patient’s subsequent 6MWD on therapy should improve24
  • It is influenced by several factors, such as age, weight, co-morbidities, need for O2 , sex, height, learning curve, and motivation7
  • The 6MWT remains the most widely used exercise test in PH centers7
    • It is an integral component for assessing prognosis and treatment effect
    • Easy to perform
    • Inexpensive and familiar to patients and centers

Findings from the REVEAL Registry provide clear evidence that changes in 6MWD impact survival in PAH (see figure below)

  • Worsening 6MWD was associated with decreased survival at 12 months among newly diagnosed PAH patients24
  • Higher survival rates were seen in patients whose 6MWD increased or remained unchanged over 12 months24

Survival Estimates by Percentage Change in 6MWD in the REVEAL Registry24†

†Data are from the Registry to Evaluate Early and Long-term PAH disease management (REVEAL Registry), a large, multicenter, prospective cohort registry that included 54 centers in the United States. 2,967 patients were enrolled between March 2006 and September 2007, all with newly or previously diagnosed World Health Organization group I PAH and pre-specified hemodynamic criteria by right-heart catheterization test.

Impact of Change in Functional Class

Changes in FC have also been shown to have an effect on survival.25

  • A European retrospective database study of PAH patients showed that stable FC I-II patients achieved the best transplantation-free survival rates at 5 years (see figure below)25

Survival Stratified by Changes in FC in a European Cohort25*

*The Hanover Medical School in Germany prospectively gathered data on all patients with newly diagnosed IPAH between 1999 and 2009 who had undergone at least one follow-up right heart catheterization within the first year after PAH-targeted therapy had been initiated. 109 patients with IPAH were selected from a cohort of patients with IPAH treated during the observation period at the center. Limitations include: risk stratification did not account for all variables in 2015 ESC/ERS guidelines, baseline and follow-up assessments were not standardized; therefore, missing follow-up data may have increased risk of selection bias, enrolled patient populations differed between registries and prospective studies are needed to validate risk parameters.

  • Patients who improved to FC I-II from III-IV did better than those who stayed in FC III-IV25
  • Stable FC III-IV patients and those with worsening functional class had markedly decreased rates of survival25

Moving From Intermediate to Low-Risk

A 2017 analysis of the Swedish PAH Register (SPAHR) revealed that PAH risk status change from baseline to follow-up had a significant impact on survival.26*

  • These results demonstrate the survival benefit when the goal of treatment is to move patients to low-risk status

*The Swedish PAH Register (SPAHR) is a register-based observational, retrospective cohort study from 2008 to 2016, which included 530 patients with PAH. Limitations include: risk stratification did not account for all variables in 2015 ESC/ERS guidelines, baseline and follow-up assessments were not standardized; therefore, missing follow-up data may have increased risk of selection bias, enrolled patient populations differed between registries and prospective studies are needed to validate risk parameters.

Survival Estimates by Risk Status at Follow-Up in SPAHR26

  • For those patients who improved to low-risk, survival was 96% at 5 years26
  • Patients who worsened to intermediate-risk or high-risk had markedly reduced survival: 43% at 5 years26
  • For the entire study cohort, survival was better (P<0.001) for patients with a higher proportion of variables at low-risk at follow-up26

Clinical Deterioration and Risk Assessment in PAH

The rate of disease progression should be considered as an important part of risk assessment.7

  • Patients who appear clinically stable may continue to have RV deterioration in many cases7
  • It is important to recognize rapid deterioration as it is indicative of a high-risk patient7

4WHAT IS THE THERAPEUTIC MANAGEMENT?

What Are the Pharmacologic Approaches for PAH Management?

There are multiple pathophysiologic pathways that have been implicated in the pathogenesis of PAH with current therapies focusing on the imbalance of vasoconstriction and vasodilation (prostacyclin deficiency).27

  • Three primary pharmacologic pathways are leveraged for managing PAH: the nitric oxide, prostacyclin, and endothelin pathways (see figure below)7
  • These pathways correspond to important therapeutic targets in PAH and play a role in determining which class of drugs should be selected28

The Three Primary Treatment Pathways14,29

Nitric oxide pathway

PDE-5 inhibitors increase cGMP, while soluble guanylate cyclase stimulators enhance cGMP production.
Both induce vasodilation

Prostacyclin pathway

Prostacyclin-class therapies result in vasodilation and inhibition of platelet aggregation and smooth muscle cell proliferation

Endothelin pathway

Endothelin receptor antagonists prevent vasoconstrictive and endothelium proliferative effects

cGMP=cyclic guanosine monophosphate; PDE-5=phosphodiesterase type 5.

The Role of Prostacyclin in PAH

Prostacyclin is mainly produced by pulmonary endothelial cells and is essential to normal lung function.27

  • Patients with PAH may have low levels of prostacyclin synthase, which could disrupt vascular homeostasis27

2015 ESC/ERS Guidelines Recommendations

Double or triple sequential therapy can be considered for patients with inadequate response to initial therapy.7

  • Although many patients with PAH benefit from the available PAH therapies, a sub-set of patients experience minimal to no improvement after therapy is initiated and others may experience clinical deterioration after initial improvement7
  • If treatment goals are not met, the therapy is considered inadequate and additional therapy may be added until the desired clinical results are achieved7
  • Patients also can be considered for referral for lung transplantation7

Adapted Treatment Algorithm7

CCB=calcium channel blockers; DPAH=drug-induced PAH; FC=functional class; HPAH=heritable PAH; IPAH=idiopathic PAH; IV=intravenous; PCA=prostacyclin analogue; WHO=World Health Organization.

*Per AMBITION protocol.30

†IV epoprostenol should be prioritized as it has reduced the 3-month rate for mortality in high-risk PAH patients, also as monotherapy.

‡Consider also balloon atrial septostomy.

§Inadequate response should be considered as an achievement/maintenance of an intermediate-risk profile based on the 2015 ESC/ERS guidelines.

Evidence-Based Treatment Algorithm

The treatment of patients with PAH is characterized by a multi-step strategy that includes the initial evaluation of severity and the subsequent response to treatment.31

The current treatment strategy for patients with PAH can be divided into three main steps31:

  • 1

    General measures, supportive therapy, referral to expert centers, and acute vasoreactivity testing for the indication of chronic calcium-channnel blocker (CCB) therapy

  • 2

    Initial therapy with high-dose CCB in vasoreactive patients or drugs approved for PAH in non-vasoreactive patients

  • 3

    Based on response to initial treatment strategy, if inadequate response, combinations of approved drugs and lung transplantation are proposed

5ADDITIONAL RESOURCES

6REFERENCES

  1. Elliot CA, Kiely DG. Pulmonary hypertension. Contin Educ Anesth Crit Care Pain. 2006;6(1):17-22.
  2. Palevksy HI. The early diagnosis of pulmonary arterial hypertension: can we do better? Chest. 2011;140(1):4-6.
  3. Brown LM, Chen H, Halpern S, et al. Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry. Chest. 2011;140(1):19-26.
  4. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107(2):216-223.
  5. Ross CA. Pulmonary arterial hypertension: early recognition and treatment can make a lifetime difference for your patient. J Nurse Pract. 2007;3(6):404-409.
  6. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114(13):1417-1431.
  7. Galiè N, Humbert M, Vachiery JL, et al; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119.
  8. Galiè N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. Eur Heart J. 2004;25(24):2243-2278.
  9. Mandras SA, Ventura HO, Corris PA. Breaking down the barriers: why the delay in referral for pulmonary arterial hypertension? Ochsner Journal. 2016;16(3):257-262.
  10. Sweiss NJ, Hushaw L, Thenappan T, et al. Diagnosis and management of pulmonary arterial hypertension in systemic sclerosis. Curr Rheumatol Rep. 2010;12(1):8-18.
  11. Rich JD, Rich S. Clinical diagnosis of pulmonary hypertension. Circulation. 2014;130(20):1820-1830.
  12. Pulmonary Hypertension RN website. Blood Tests. http://pulmonaryhypertensionrn.com/blood-tests/. Updated January 2018. Accessed November 26, 2018.
  13. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(suppl 25):D42-D50.
  14. McLaughlin VV, Archer Sl, Badesch DB, et al. American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573-1619.
  15. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-387.
  16. Farber HW, Miller DP, Poms AD, et al. Five-year outcomes of patients enrolled in the REVEAL Registry. Chest. 2015;148(4):1043-1054.
  17. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-387.
  18. Farber HW, Miller DP, Meltzer LA, et al. Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the REVEAL Registry. J Heart Lung Transplant. 2013;32(11):1114-1122.
  19. Barst RJ, Chung L, Zamanian RT, et al. Functional class improvement and 3-year survival outcomes in patients with pulmonary arterial hypertension in the REVEAL Registry. Chest. 2013;144(1):160-168.
  20. Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2):1-10
  21. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2015;46(4):903-975.
  22. Crapo RO, Casaburi R, Coates AL, et al. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-117.
  23. Barnett CT, Jackman JS, Moore NC, et al. The effect of walking path configuration on six-minute walk test performance and gait variability: a pilot study. Gait & Posture. 2015;42(3):S54.
  24. Farber HW, Miller DP, McGoon MD, et al. Predicting outcomes in pulmonary arterial hypertension based on the 6-minute walk distance. J Heart Lung Transplant. 2015;34(3):362-368.
  25. Nickel N, Golpon H, Greer M, et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2012;39(3):589-596.
  26. Kylhammar D, Kjellström B, Hjalmarsson C, et al. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension [published online ahead of print June 1, 2017]. Eur Heart J. doi:10.1093/eurheartj/ehx257.
  27. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327(2):70-75.
  28. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425-1436.
  29. Sitbon O, Morrell N. Pathways in pulmonary arterial hypertension: the future is here. Eur Respir Rev. 2012;21(126):321-327.
  30. Galiè N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834-844.
  31. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(suppl 25):D60-D72.
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This MPR/PulmonologyAdvisor Fact Pack is produced as a basic reminder of important information for healthcare professionals. Readers are advised to consult manufacturers and specialists if questions arise about specific products, treatments, or diseases. The publisher and editors do not assume liability for any errors or omissions. MPR, PulmonologyAdvisor, and Fact Pack are registered trademarks of Haymarket Media, Inc.

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