By Micah Fisher, MD
The area of pulmonary hypertension has seen an ex-plosion in interest and therapeutic options over the past 25 years. The first World Health Organization (WHO) international symposium was held in 1973, leading to a standardized definition, a classification system and calls for further investigation. That first classification system, dividing patients between primary and secondary pulmo-nary hypertension, has since been expanded significantly as we have developed a better understanding of the different types of pulmonary hypertension.
The current WHO classification system, last modified in 2013, consists of five types of pulmonary hypertension: 1. Pulmonary arterial hypertension, 2. Pulmonary hyper-tension due to left heart disease, 3. Pulmonary hypertension due to chronic hypoxemia and respiratory diseases, 4. Chronic thromboembolic pulmonary hypertension, and 5. Pulmonary hypertension due to multi-factorial or unclear mechanisms. While our understanding of all these types has improved significantly, at this point, we only have effective targeted therapy for types 1 and 4.
Idiopathic pulmonary arterial hypertension, formerly known as primary pulmonary hypertension, is the prototypic form of pulmonary arterial hypertension. This remains a rare disease with prevalence estimates around 6 people/million. Survival with modern therapy has significantly improved compared to original descriptions, which showed a median survival of 2.8 years.
We now have multiple drug options in each of the three main pathophysiologic pathways, including oral, inhaled, subcutaneous infusions and continuous intravenous infu-sion therapies. These therapies have been very effective in significantly reducing the need for lung transplantation.
Despite the opportunities for ongoing education prompted by the advances in therapeutics, there remains a significant challenge in assuring the right diagnosis is made and appropriate therapy is started. This was highlighted by the multi-center study by Deano et al., published in 2013, which showed that a third of patients who had been given a diagnosis prior to referral had been misdiagnosed, and that more than 50 percent of the patients who had been started on therapy were receiving it contrary to guidelines.
Given the significant side effects and expense of these therapies – some of them costing $150,000 or more a year –this is an issue that needs greater emphasis. Despite our increased understanding, appropriate diagnosis and management remains challenging, which is why all of the major pulmonary hypertension guidelines recommend referral to a center with expertise in managing these patients.
Since the approval of riociguat, an oral soluble guanylate cyclase stimulator, for chronic thromboembolic pulmonary hypertension (CTEPH) in 2013, this disease has received a lot more attention. CTEPH occurs in patients who have incomplete dissolution of pulmonary emboli, leading to chronic pulmonary vascular obstruction and resultant pulmonary hypertension. This appears to be a relatively uncommon complication of pulmonary embolic disease, with most studies suggesting a prevalence between 1 percent and 4 percent of patients followed prospectively after acute pulmonary embolism.
Interestingly, upwards of 50 percent of patients diagnosed with CTEPH will not have a clear history of deep vein thrombosis or pulmonary embolism prior to diagnosis.
Subsequently, all patients being evaluated for pulmonary hypertension, regardless of history of venous thromboembolism are recommended to be screened for CTEPH with a ventilation perfusion scan, which has significantly better sensitivity compared to a CT scan.
Patients diagnosed with CTEPH should be further assessed for surgical candidacy. The operation, a pulmonary endarterectomy, is a major surgery only performed with expertise at a few centers nationwide. The world leader in this operation is the University of California at San Diego, where they perform several hundred annually with published perioperative mortality ranging from 2 percent to 4 percent based on preoperative hemodynamics. Most patients have normalization or near normalization of their pulmonary hemodynamics with surgery and have normal life expectancy after successful surgery, with the only ca-veat that they must remain on life-long anticoagulation.
For years, the only options for CTEPH patients was a pulmonary endarterectomy or lung transplantation. Therapies that had been shown to be effective for pulmonary arterial hypertension had unimpressive results when trialed in patients with CTEPH. That was until riociguat was shown to improve hemodynamics and functional capacity in patients who had inoperable disease or had significant residual pulmonary hypertension after surgery. While these outcomes were robust, they are small compared to the potential outcomes from surgery at an expert center and should not be used to justify not referring patients for a more definitive surgical treatment.
The field of pulmonary hypertension has changed significantly in recent years with updates to the classification system and multiple new therapies. This has led to a significant increase in education targeted at multiple providers. While this has increased awareness, it has also led to a significant amount of over-diagnosis and over-prescribing. Despite these advances, patients with pulmonary hypertension continue to be a diagnostic and management challenge necessitating referral to a pulmonary hypertension center.