Mimics Hinder Early Evaluation for Pulmonary Hypertension
Differential diagnoses, missed red flags and obsolete monotherapies are potential pitfalls in pulmonary hypertension care
The first World Symposium on Pulmonary Hypertension (WSPH) was convened in 1973 by the World Health Organization. Fifty years later, significant improvements in the understanding of pathogenesis, better clinical diagnostics, and a growing array of treatment options and protocols have greatly changed the management of pulmonary hypertension (PH).
Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services Policy
Pulmonary medicine specialist Franck Rahaghi, MD, has witnessed much of the change as Director of the Pulmonary Hypertension Clinic at Cleveland Clinic Weston Hospital, a program he’s led since 2003, and as a clinical researcher involved in the development of more than a third of PH medications currently approved for use in the United States.
“While we can do a lot more for patients today, pulmonary hypertension remains a chronic progressive disorder that often results in heart failure and death, especially when it goes undiagnosed,” says Dr. Rahaghi. “We need to instill a much higher level of clinical suspicion of PH for patients to fully benefit from the advancements we’ve made.”
Pulmonary hypertension represents a group of pulmonary vascular disorders characterized by high blood pressure in the pulmonary arteries that results in reduced blood flow through the lungs and lower blood oxygen levels. The current iteration of the classification system, presented at the 5th WSPH in 2013, categorizes PH into the following 5 groups, all of which are associated with increased morbidity and mortality.
“Left-sided heart disease and lung disease are by far the most common causes of pulmonary hypertension and account for the increasing incidence of the disease,” says Dr. Rahaghi, noting this will continue to be the case with an aging population.
Another major update out of the 6th WSPH in 2018 saw the hemodynamic definition of PH lowered from a mean pulmonary artery pressure (mPAP) of at least 25 mm Hg to an mPAP of more than 20 mm Hg 14. More recently, European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines (2022) also lowered the threshold of pulmonary vascular resistance from 3 Wood units to 2.
“This means even more people with PH are out there,” says Dr. Rahaghi. “If we can get them evaluated and start treatment earlier, we can slow their disease progression and protect their quality of life while extending that life.”
Early clinical presentation of PH include exertional dyspnea, fatigue, and weakness. Later symptoms may include chest pain, dizziness and fainting, heart palpitations, and lower extremity edema.
“Because this generalized symptomology has many potential causes, including asthma and COPD, patients with PH often experience a delay in diagnosis,” says Roger Alvarez, DO, a pulmonary medicine specialist who joined Cleveland Clinic Weston Hospital earlier this year and is leading the establishment of the hospital’s Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Program.
“I frequently see patients who have suffered with symptoms for years before being referred for suspected PH,” says Dr. Alvarez. “The most important symptoms that should trigger suspicion are lightheadedness, dizziness or syncope, when they occur with exertion.”
He also notes some red flags that merit a quick referral for a PH evaluation.
“Because of the many conditions that can mimic PH symptoms, patient follow-up is essential,” adds Dr. Alvarez. “First-line providers need to emphasize to patients that if they don’t get better with initial treatments, they need to come back as other conditions may be at work.”
While group 2 and group 3 pulmonary hypertension are the most common, more than half of the patients treated at Weston Hospital have the rarer form, PAH (group 1), which causes vasoconstriction and vascular remodeling of the distal pulmonary arteries. This group is further divided into seven subgroups, including idiopathic, hereditary, and drug- and toxin-induced PAH, among others.
There is no cure for PAH, and only about 500-1000 new cases are diagnosed each year in the U.S., according to the American Lung Association.
“Although PAH is very rare, we actually have a lot more to offer in terms of PAH-specific treatments,” explains Dr. Alvarez. “Today we can control symptoms using different medical therapies that target one of three physiologic pathways involved in PAH pathogenesis, which are the nitric oxide, prostacyclin, and endothelin pathways.”
Since the first oral therapy for pulmonary hypertension was approved in 2001, many other therapies quickly followed, including treprostinil, a prostaglandin analog, endothelin receptor antagonists (ERA), and phosphodiesterase type 5 inhibitors (PDE5i), like tadalafil. Riociguat, a soluble guanylate cyclase (sGC) stimulator, was approved in 2013 and is used for treating PAH as well as CTEPH that cannot be treated surgically.
WSPH guidelines issued in 2018 supported the initiation of combination therapy, a more aggressive form of therapy. This approach was backed in 2022 by ESC/ERS guidelines that simplified the treatment algorithm for PAH and promoted initial combination therapy and treatment escalation.
Just this year, Dr. Rahaghi teamed with other PAH researchers to publish a study in the May 2023 issue of Respiratory Medicine on the use of riociguat with an ERA for upfront combination therapy in patients with PAH at intermediate to high risk of 1-year mortality. The team also looked at the benefits of switching to riociguat from a PDE5i in patients at intermediate risk who are not achieving treatment goals with PDE5i-based dual combination therapy.
“Currently PDE5i or ERA monotherapy and PDE5i plus ERA combinations are the most frequently used approaches to treating PAH,” says Dr. Rahaghi. “Here at Weston Hospital, however, we rarely use initial monotherapy in favor of dual therapies. We’ll also escalate to triple therapy for high-risk patients who do not reach treatment goals with the initial combo therapy.”
Dr. Alvarez cautions that while many patients benefit from more aggressive combination therapy, older patients with multiple comorbidities may require a more traditional stepwise approach. “We always have to consider the patient’s risk profile and personal preferences, treatment adherence and tolerance, and other factors, to ensure we are delivering the best, patient-centered care,” he adds.