Cohort Definition Name: “Pulmonary Arterial Hypertension”
Contributor name: Joel N. Swerdel
Contributor OrcId: 0000-0001-9491-2737
Logic Description: First occurrence of Pulmonary Arterial Hypertension.
Recommended study application: outcome, indication
Assertion statement: This cohort definition was executed on at least one real person-level observational health data source and resulted in a cohort with at least 1 person.
Submitted cohort definition:
pah.txt (49.4 KB)
Target Clinical Description
Overview
Pulmonary Arterial Hypertension (PAH) is a rare, progressive and life-threatening disorder that may lead to an untimely death if undiagnosed or left untreated (Montani et al. 2013, Brown et al. 2011). Elevated blood pressure induced by thickening and narrowing of the small pulmonary arteries over time causes vascular and cardiac remodelling, which ultimately may lead to right heart failure if left without proper disease management (Montani et al. 2013).
A recent critical appraisal of the literature reported epidemiology estimates of approximately 5.8 adult patients per million for PAH incidence and 47.6 to 54.7 per million for PAH prevalence (Leber 2021) using recent (<5 years) national systematic registry data from centralized healthcare systems (NHS Digital 2021, Kjellström 2020).
Pulmonary arterial hypertension can be further classified into subtypes according to etiology. These are idiopathic PAH (IPAH), heritable PAH, PAH induced by exposure to drugs and toxins, or PAH associated with other conditions, such as connective tissue disease (CTD-PAH) and congenital heart disease (CHD-PAH). For the most common PAH subtypes, incidences and prevalences per million population are reported in systematic national registries: for IPAH 2.6 to 7.6 and 9.0 to 18.3; CTDPAH 2.8 and 10.0 to 13.0; and CHD-PAH 2.2 and 7.0 to 19.0, respectively (Peacock 2007, Skride 2018, NHS Digital 2021).
Presentation
PAH symptoms
Common symptoms of PAH are chronic unexplained dyspnea or shortness of breath, fatigue, nonproductive cough, angina pectoris, fainting or syncope, peripheral edema, rarely hemoptysis, and other signs and symptoms of cardiovascular decompensation.
PAH risk factors
Any factor or condition that is suspected to play a predisposing or facilitating role in the development of the disease is defined as a risk factor. A number of risk factors for the development of PAH have been identified that include family history, drugs and chemicals, diseases, age, and sex (Simonneau 2019).
Idiopathic/Hereditary PAH: Idiopathic PAH corresponds to sporadic disease in which there is neither a family history of PAH nor an identified risk factor, and represents the most frequent form of PAH. When PAH occurs in a familial context, germ-line mutations in the bone morphogenetic protein receptor type 2 gene, a member of the transforming growth factor beta signaling family, can be detected in approximately 70% to 80% of cases. Mutations of this gene can also be detected in 10% to 20% of apparently sporadic cases, thus representing the major genetic predisposing factor for PAH (Morrell 2019).
Drug- and Toxin-induced PAH: There are several well-known toxin and drug risk factors for PAH, including aminorex, fenfluramine derivatives, methamphetamines, dasatinib, and toxic rapeseed oil. Possible associations are suspected for cocaine, phenylpropanolamine, L-tryptophan, St John’s wort, amphetamines, interferon α and β, alkylating agents, bosutinib, directacting antiviral agents against hepatitis C virus, leflunomide, and indirubin (Simonneau 2019).
Pulmonary Arterial Hypertension Associated With Underlying Conditions/Diseases: Pulmonary arterial hypertension may also occur associated with other diseases. Associated PAH includes connective tissue diseases (CTDs), CHD, portopulmonary hypertension (PoPH), HIV infection, and schistosomiasis (Humbert 2022, Galiè 2015b). Frequent causes of PAH in countries where these diseases are still endemic are schistosomiasis, HIV infection, post-streptococcal rheumatic heart disease, and sickle cell disease (Hoeper 2016a).
CTD-PAH represents about 15% to 25% of adult patients with PAH. Several CTDs are associated with PAH, such as mixed CTD and systemic lupus erythematosus (SLE) but is most commonly seen with systemic sclerosis (Mukerjee 2003, Hachulla 2005, Humbert 2006, Escribano-Subias 2012, Hoeper 2016a).
A significant proportion of patients with CHD, in particular those with relevant systemictopulmonary shunts, will develop PAH if left untreated (Simonneau 2013). Eisenmenger syndrome (ES) represents the most advanced form of CHD-PAH (Simonneau 2013). CHD-PAH represents about 7% to 15% of cases in the adult PAH population (Humbert 2006, EscribanoSubias 2012, Hoeper 2016a).
Portopulmonary hypertension is a form of PAH associated with portal hypertension with or without underlying chronic liver disease. In the French PH Network registry, PoPH represented 18% of all PAH patients, the majority of whom had alcohol-related cirrhosis (58%) (Savale 2020).
Pulmonary arterial hypertension associated with PoPH accounted for 4.9% in the US REVEAL Registry (Krowka 2012).
Pulmonary arterial hypertension is a rare complication of HIV infection (Simonneau 2013). In France, the prevalence of this condition was estimated at 0.5% of the PAH population in 2005 (Sitbon 2008).
Common comorbidities
The co-occurrence of PAH and comorbidities increases the complexity of disease management for patients who may require multiple pharmacological interventions to treat both PAH and the comorbidity. In PAH, approximately three quarters of patients have at least one comorbidity, with patients aged 65 years and over having a greater number of comorbidities. Current research suggests that the presence of comorbid conditions in patients with PAH negatively affects outcomes (Lang 2019).
A variety of comorbid conditions, not representing the principal cause of the development of PAH, have been identified in patients with PAH. The US REVEAL Registry (2006 to 2007) reported the following comorbidities in more than 10% of all IPAH patients: systemic hypertension, obesity, sleep apnea, clinical depression, obstructive airway disease, thyroid disease, diabetes mellitus, and ischemic cardiovascular events (Lang 2019). In the US Pulmonary Hypertension Scientific Registry conducted almost 10 years later (2015 to 2018), obesity, diabetes, hypertension, hypothyroidism, and clinical depression were found to be among the most common comorbid conditions (Badlam 2021).
Additional comorbidities associated with PAH include anemia, chronic kidney disease, chronic liver disease, chronic pain, chronic muscle disease, frailty, peripheral vascular disease, cancer, dementia, cirrhosis, renal insufficiency, and atrial fibrillation (Lang 2019). The main causes of death reported in PAH patients are cardiovascular events, including heart failure and sudden death, which account for 44% to 89% deaths in PAH patients (Tonelli 2013, Ruiz-Cano 2009).
Patients with PAH may develop various severe liver complications (due to severe congestive hepatopathy induced by right heart failure and/or due to autoimmune disease/CTD) (Wells 2018, Nickel 2021).
Assessment
Diagnosis of PAH requires right heart catheterization, an invasive procedure that is associated with a small (<1%) risk of major complications.(Humbert 2022, Galiè 2015) Therefore, physicians are recommended to initially investigate for PH (incl. PAH) using non-invasive tests. Transthoracic echocardiography is recommended for all patients with suspected PH and, as such, is considered the gold-standard screening test for PH.(Humbert 2022, Galiè 2015) The diagnosis of PH does not rely on these two tests alone; evidence of PH, its severity and/or underlying aetiology can be gleaned from investigations such as electrocardiogram, chest radiography, and pulmonary function tests.(Humbert 2022, Galiè 2015) However, delays in diagnosis arise at every stage of the journey, starting with the time between patients noticing symptoms and seeing a doctor, with almost half (47%) of patients waiting over six months.(Armstrong 2019)
Plan
Supportive Therapy
A range of conventional therapies have been shown to provide some degree of symptomatic benefit to PAH patients. However, they have a limited effect on the disease process or prognosis.
Among those conventional treatments are oxygen for patients with dyspnea associated with PAH, anticoagulants to decrease the risk for intrapulmonary thrombosis and thromboembolism, diuretics for patients with decompensated right heart failure associated with PAH, and calcium channel blockers, which may be of benefit in PAH patients with a positive vasoreactive response during right heart catherization (Simonneau 2019, Fuso 2011).
Advanced Therapy (Also Termed PAH-specific Therapy)
Pulmonary arterial hypertension-specific therapies target one of three major pathways known to be involved in the development of PAH: the prostacyclin and nitric oxide pathways, which are underexpressed in patients with PAH, and the ET pathway, which is overexpressed. Route of administration varies between the drugs (intravenous, subcutaneous, oral, or inhaled). These PAH-specific therapies are either prescribed alone or in combination, which can be either provided as initial or sequential therapies (Galiè 2019).
Phosphodiesterase-5 inhibitors: these oral agents act on the nitric oxide pathway to induce vasodilation. They also have antiproliferative effects on vascular smooth muscle cells. A systematic review and meta-analyses of clinical trials reported that treatment with PDE-5 inhibitors has a beneficial effect on exercise capacity, hemodynamic parameters, WHO FC, and survival in patients with PAH (Barnes 2019).
Endothelin receptor antagonists (ERAs): Endothelin (ET) is implicated in the pathogenesis of PAH through its actions on the pulmonary vasculature. ET is elevated in patients with PAH and levels are directly related to disease severity and prognosis. Endothelin receptor antagonists are oral treatments that act by blocking the binding of ET to either one (single antagonist) or both (dual antagonist) of its receptors. Clinical trials have shown that treatment with ERAs has a beneficial effect on exercise capacity, WHO FC, hemodynamics, and time to clinical worsening in patients with PAH (Mehta 2017, Pulido 2013). Currently marketed ERA therapies are bosentan (dual antagonist), macitentan (dual antagonist), and ambrisentan (single antagonist).
Drugs targeting the prostacyclin pathway: synthetic prostacyclins (eg, epoprostenol), prostacyclin analogs (eg, treprostinil, beraprost, iloprost), and prostacyclin receptor agonists (eg, selexipag) act by correcting the deficiency of endogenous prostacyclin seen in patients with PAH. The clinical use of intravenously administered prostacyclins in patients with PAH has been extended by the synthesis of more stable analogs that can be given by subcutaneous infusion, by inhalation, or by oral administration. Clinical trials with prostacyclin and prostacyclin analogs have shown improvement in PAH symptoms (eg, epoprostenol, iloprost, treprostinil), exercise capacity (eg, beraprost, epoprostenol, iloprost, treprostinil), hemodynamics (eg, epoprostenol, iloprost, treprostinil, selexipag), and survival (eg, epoprostenol, selexipag) (Sitbon 2015, Galié 2015a).
Soluble guanylate cyclase (sGC) stimulator (riociguat) acts in synergy with endogenous nitric oxide and directly stimulates sGC to produce intracellular cyclic guanosine monophosphate, which influences vascular tone, proliferation, fibrosis, and inflammation. Short-term clinical trials (12 weeks) have demonstrated a statistically significant improvement in exercise capacity, WHO FC, and delay in clinical worsening with riociguat (Humbert 2022, Galiè 2015c).
Prognosis
Pulmonary arterial hypertension is a disease of the small pulmonary arteries, characterized by vascular proliferation and remodeling. These vascular changes result in a progressive increase of PVR leading to right ventricular failure and premature death. PAH can be treated with PAH-specific medication, but there is currently no cure for the disease. With disease progression, exercise tolerance is markedly decreased, and life expectancy is reduced (Humbert 2022, Galiè 2015b).
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