Ace the Case: A 53-Year-Old Woman with Shortness of Breath on Exertion

Clinical Review

Clinical Review

Pulmonary arterial hypertension is a complex disease, affecting at least 15 per 1 million people worldwide and causing significant morbidity and mortality.1,2 Without treatment, mean survival is 2.8 years.2,3 Pulmonary arterial hypertension is a subtype of a larger group of pulmonary hypertension conditions. Five types of pulmonary hypertension exist: Group 1 (pulmonary hypertension, also called PAH) is pulmonary hypertension not due to a primary cardiac, pulmonary, or thromboembolic disease; Group II is caused by left-sided heart disease; Group III is associated with chronic lung disease; Group IV is secondary to chronic thrombotic or embolic disease; and Group V is a miscellaneous category.2

Group 1 pulmonary hypertension is idiopathic in 60% of cases.2 Pulmonary arterial hypertension is more common in women and is typically diagnosed around age 50 years.4 Morbidity and eventual death are caused by progressive pulmonary vascular endothelial proliferation and vasoconstriction that results in right-sided heart failure. Three pathways are implicated in the pathophysiology of PAH: endothelin, prostacyclin, and nitric oxide.5

Endothelin-1 is a vasoconstrictor and promoter of pulmonary artery smooth muscle cell proliferation. Although endothelin-1 itself is not upregulated in patients with PAH, its receptors are, which leads to excessive vascular proliferation and vasoconstiction.5 In patients with PAH, both prostacyclin synthase, which is responsible for the creation of prostacyclin (a pulmonary vasodilator), and prostacyclin metabolites are abnormally decreased.5 Finally, the nitric oxide pathway, which causes vasodilation, is impaired in patients with PAH. Phosphodiesterase-5, which is an inactivator of cyclic guanosine monophosphate, is upregulated in PAH, causing increased degradation of cyclic guanosine monophosphate and less vasodilation.5

Symptoms of PAH are often nonspecific, making early diagnosis challenging. Approximately 86% of patients present with dyspnea on exertion.3 As the disease progresses, patients begin to experience chest pain, syncope, early satiety, abdominal bloating, and edema.6 Physical examination may be normal in early disease.

Although most cases are idiopathic, patients with systemic sclerosis, infectious diseases such as schistosomiasis and human immunodeficiency virus, congenital heart disease, portal hypertension, illicit drug use, or a family history of PAH are at an increased risk.6-9 Clinicians should have a high index of suspicion in patients with these risk factors who present with shortness of breath or fatigue.

Screening tests such as electrocardiogram, chest radiograph, pulmonary function tests, and laboratory tests are nonspecific and even normal.3,6-7 An echocardiogram is warranted if PAH is suspected based on history, physical examination, or other testing.6 Although not diagnostic for PAH, an echocardiogram can stratify one’s risk and identify patients who require a right-heart catheterization (the gold standard for diagnosis) and/or a referral to an advanced pulmonary hypertension treatment center.3,6-7

An echocardiogram classifies the patient as low-, intermediate-, or high-risk PAH based on the velocity of the peak tricuspid regurgitation and the presence of “PH signs” on the echocardiogram.1 Current guidelines list 7 PH signs: right ventricular or left ventricular basal diameter ratio >1.0, flattening of the interventricular septum (left ventricular eccentricity index >1.1), right ventricular outflow Doppler acceleration time <105 milliseconds or midsystolic notching, early diastolic pulmonary regurgitation velocity >2.2 m/s, pulmonary artery diameter >25 mm, inferior vena cava diameter >21 mm with decreased inspiratory collapse, and an end-systole right atrial area >18 cm2.1

Definitive diagnosis is then made with a right-heart catheterization.1 Pulmonary hypertension in general is diagnosed based on a mean pulmonary artery pressure of 25 mm Hg at rest. Pulmonary arterial hypertension is characterized by the presence of precapillary pulmonary hypertension, which is defined by an end-expiratory pulmonary artery wedge pressure ≤15 mm Hg and a pulmonary vascular resistance >3 Wood units.2 Additional hemodynamic testing is performed, and all patients are screened for vasoreactivity (important for treatment decisions later). Right-heart catheterization should be performed with the pressure transducer zero level at the midthoracic line or at the level of the left atrium. Left-heart disease must be excluded (as these patients are classified as Group II pulmonary hypertension and are treated differently).

Once a diagnosis of PAH is made, additional testing is performed to classify patients into a risk category. (This is different than the echocardiogram risk categories previously mentioned.) Patients are classified as low-, intermediate-, or high-risk PAH, all of which have different mortality rates and different treatment recommendations.1,8,11 In addition to an echocardiogram and a right-heart catheterization, patients undergo a 6-minute walk distance (6MWD) test and cardiopulmonary exercise testing and have brain natriuretic peptide (BNP) levels drawn.1,8,11 The World Health Organization (WHO) functional heart failure class is also determined based on patients’ symptoms.1,8,11

Low-risk patients have a 1-year mortality less than 5% and meet the following criteria:1,8,11

  • No clinical signs of right ventricular heart failure, progression of symptoms, or syncope
  • WHO functional class I-II
  • 6MWD >440 m
  • Cardiopulmonary exercise testing: peak VO2, >15 mL/min/kg (over 65% predicted); VE/VCO2 slope, <36
  • BNP <50 ng/L; NT-proBNP <300 ng/L
  • Echocardiogram: Right atrial area <18 cm2 and no pericardial effusions
  • Hemodynamics: Right atrial pressure, <8 mm Hg; cardiac index, ≥2.5 L/min/m2; SvO2, >65%

Intermediate-risk patients have a 1-year mortality of 5% to 10% and meet the following criteria:1,8,11

  • No clinical signs of RV heart failure
  • Slow progression of symptoms and occasional syncope
  • WHO functional class III
  • 6MWD between 165-440 m
  • Cardiopulmonary exercise testing: peak VO2, 11-15 mL/min/kg (35% to 65% predicted); VE/VCO2 slope: 36-44.9
  • BNP 50-300 ng/L; NT-proBNP 300-1400 ng/L
  • Echocardiogram: RA area between 18-26 cm2 and no or minimal pericardial effusions
  • Hemodynamics: RAP, 8-14 mm Hg; cardiac index, 2-2.4 L/min/m2; SvO2, 60%-65%

High-risk patients have a 1-year mortality >10% and meet the following criteria:1,8,11

  • Signs of RV heart failure
  • Rapid progression of symptoms and repeated syncope
  • WHO functional class IV
  • 6MWD <165 m
  • Cardiopulmonary exercise testing: peak VO2, <11 mL/min/kg (<35 predicted); VE/VCO2 slope, ≥45
  • BNP >300 ng/L; NT-proBNP >1400 ng/L
  • Echocardiogram: RA area >26 cm2 and pericardial effusions present
  • Hemodynamics: Right atrial pressure, >14 mm Hg; cardiac index, <2.0 L/min/m2; SvO2, <60%

Treatment recommendations are based on the risk classification and the presence of vasoreactivity (previously determined on right-heart catheterization). Current standard of care is based on the 2014 American College of Chest Physicians guideline for Pharmacological Therapy for Pulmonary Arterial Hypertension in Adults and the 2015 European Society of Cardiology/European Respiratory Society guidelines.1,8

The first step is determining whether the patient would benefit from a calcium channel blocker. If criteria for vasoreactivity were met on right-heart catheterization, then the patient needs to be started on a high-dose calcium channel blocker.7,12 Calcium channel blockers are not indicated in patients without proven vasoreactivity and should not be routinely given.7,12 If the patient is non-vasoreactive, then PAH-specific treatment is indicated.

Treatments for PAH specifically target one or more of the following pathologic pathways: endothelin, prostaglandin, or nitric oxide. Upfront combination therapy refers to starting a treatment-naïve patient on 2 or 3 PAH-specific medications at once. With sequential therapy, one agent is started initially as monotherapy and additional agents are added over time.7 Most clinical trials have evaluated sequential combination therapy, adding additional drugs to a patient already taking monotherapy.13-18 However, based on recent trials, most experts recommend initial upfront therapy.19 Although the data are abundant regarding sequential combination therapy, currently only 2 randomized controlled trials comparing monotherapy to upfront combination therapy have been published.20-23

The AMBITION trial compared monotherapy ambrisentan (a selective endothelin receptor antagonist) or tadalafil (a PDE5 inhibitor acting on the nitric oxide pathway) to combination therapy ambrisentan and tadalafil in patients with a WHO functional class of II-III.20 Patients receiving the initial combination therapy had decreased rates of clinical failure compared to monotherapy with either agent alone.20 Another post-hoc analysis of the AMBITION trial data also revealed that the combination therapy was beneficial over monotherapy for patients with connective tissue disease–associated PAH.21 A smaller trial was then performed on patients with scleroderma-associated PAH, revealing that patients who received the combination therapy upfront had decreased right ventricular mass and decreased pulmonary vascular resistance.22 The BREATHE-2 trial compared epoprostenol (an intravenous prostaglandin) alone to the upfront combination of epoprostenol and bosentan (an endothelin receptor antagonist); a decrease in pulmonary vascular resistance was seen in the combination therapy group, but it did not reach statistical significance.23

Based on previous clinical trials, the following treatment recommendations have been given, stratified by risk group:

Low-Risk Patients

Patients who are treatment-naïve, low risk or who have a WHO functional class II should be started on initial upfront combination therapy. Although current published guidelines give treatment recommendations for monotherapy, many experts believe this is outdated secondary to the aforementioned clinical trials.19 If initial combination therapy is used, then ambrisentan and tadalafil have been found to be effective.20 Although only ambrisentan and tadalafil were studied in a randomized controlled trial, other endothelin receptor antagonists combined with other PDE-5 inhibitors can be considered.1

Intermediate-Risk Patients

Patients who are treatment-naïve, intermediate risk or who have a WHO functional class III should also be started on immediate combination therapy. Intermediate-risk patients who have evidence of rapid disease progression should be started on a parenteral prostanoid.8 As with low-risk patients regarding upfront combination therapy, the most evidence exists for the use of ambrisentan and tadalafil.1,8 Other combinations include bosentan, sildenafil, and intravenous epoprostenol; bosentan and intravenous epoprostenol; any ERA, any PDE-5i, and subcutaneous treprostinil; and any ERA, any PDE-5i, and an intravenous prostacyclin analogue.1,8

High-Risk Patients

Patients who are treatment-naïve, high risk or who have a WHO functional class IV should all be initiated on combination therapy with a parenteral prostanoid agent.1,8 If the patient is unable to have or does not desire intravenous therapy, an inhaled prostanoid should be used.1,8 Initial combination recommendations include bosentan, sildenafil, and intravenous epoprostenol, as well as bosentan and intravenous epoprostenol.1,8

Currently, additional trials are underway comparing upfront combination therapy to monotherapy.24,25 Another area being studied is that of initial triple combination therapy. One study of 19 patients with newly diagnosed, severe PAH suggested that triple combination therapy may improve survival in patients with advanced disease.26 The ongoing TRITON study, a Phase 3b trial, is evaluating upfront triple combination therapy in patients newly diagnosed with PAH.27

Survival is dependent on early diagnosis, before advanced disease progression. Patients diagnosed at a New York Heart functional classification (NYHFC) of I have a 5-year survival of 88%, compared to patients diagnosed with a NYHFC of IV, who only have a 5-year survival rate of 43.8%.28

Please try again. The questions you answered incorrectly are highlighted in red below.

Ms. R is diagnosed with PAH on a right-heart catheterization. She did not meet criteria for vasoreactivity and there is no evidence of pulmonary emboli. Additional testing is performed. She is found to have a 6MWD of 500 m, BNP of 40 ng/L, and NT-proBNP of 200 ng/L. Cardiopulmonary exercise testing revealed a peak VO2 of >65% predicted. What is the best initial treatment option?
Please complete this question.
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Correct Answer: C.

Rationale: This patient has low-risk PAH. Based on symptoms, she has a WHO functional class II. Her 6MWD, BNP, NT-proBNP, and cardiopulmonary exercise testing results are all consistent with low-risk PAH.1,8,11 Although epoprostenol, an intravenous prostanoid, is recommended for intermediate- and high-risk disease, it is not considered a first-line treatment for those with low-risk disease.1,8 Oral nifedipine is only indicated in patients with vasoreactivity.7,12 Although ambrisentan monotherapy could be considered, most experts recommend initial combination therapy for the treatment of all patients with PAH.19 Ambrisentan and tadalafil has been the most well-studied combination in PAH and has been shown to be superior to monotherapy for low-risk patients.1M