Pulmonary arterial hypertension (PAH) is a fatal disease that exhibits pulmonary vascular remodeling. It is characterized by progressively increasing pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). PAH eventually leads to hypoxia, right-sided heart failure, and death (1). According to guidelines, PAH is defined as a mean baseline PAP of less than 25 mm Hg, associated with pulmonary artery wedge pressure ≤15 mm Hg and elevated PVR ≥ 3 Wood units via right heart catheterization. PAH is generally classified into the following: (1) idiopathic or heritable; (2) drug or toxin-induced (aminorex, benfluorex, and toxic rapeseed oil); and (3) associated condition-induced, such as connective tissue disease, human immunodeficiency virus infection, congenital heart disease, and schistosomiasis (1). Since the 1990s, various drugs have been used to treat specific-PAH types, predominantly focusing on three pathobiological pathways: endothelin receptor antagonist (ERA), nitric oxide (NO), and prostanoids pathways (2), which significantly improve exercise capacity and cardiopulmonary parameters. These agents may be administered through the following: ingestion, inhalation, subcutaneous injection, and intravenous injection (2, 3). However, previous studies have indicated that intravenous injection can lead to embolism and thrombosis. Additionally, local pain with subcutaneous injection is a common occurrence (4–6). Although inhalation has proven to be effective and safe, only a few drugs have been recommended by the American Heart Association/European Society of Hypertension. Additionally, the inhaled drugs are often short-acting and require multiple daily doses (7). Comparatively, ingestion is commonly used and patients usually show good compliance. In 2016, a quantitative meta-analysis found that, compared to a placebo, oral drugs can ameliorate exercise intolerance, increase pulmonary vascular remodeling, and improve quality of life (8). However, sitaxsentan, an ERA that was eradicated from the market due to fatal hepatotoxicity in 2010 (9), and imatinib, a PAH medication terminated due to severe side effects (subdural hematoma), were included in the study. As a guideline for PAH, in 2018, it was proposed that the following targeted treatments be recommended: bosentan, ambrisentan, and macitentan in the ERA pathway; sidenafil, tadalafil, vardenafil, and udenafil in the NO pathway; and iloprost, beraprost, selexipag, and treprostinil in the prostanoids pathway (10). With studies [Fu et al. (11); etc.] indicating more proof about the efficacy and safety of targeted drugs of each type, including ingestion, inhalation, subcutaneous injection, and intravenous injection, focus has been put on the oral drugs as these are important treatments for PAH therapy. Early in 2018, Zheng et al. (12) meta-analyzed 25 randomized controlled trial (RCTs) about oral targeted therapies in PAH, showing the benefits of oral treatments on clinical worsening events (CWEs) in PAH. Accordingly, to provide the most suitable strategy for PAH populations with specific clinical characteristics for precision treatment, more detailed subgroup analyses are required. Hence, we conducted a meta-analysis and pooled data from clinical trials comparing oral PAH-specific drugs with placebo to assess the efficacy and safety of these treatments in different age groups and different functional classes (FCs).

Pulmonary arterial hypertension is a life-threatening disorder, and the 5-year survival rate is less than 60% (47). An approved drug could lengthen the lifespan of patients, but it cannot reverse the development of the disease. Targeted drugs, such as those that affect ERA, NO, and prostanoids pathways, are still the recommended therapy for PAH patients (2). As such, they have been shown to slow PAH progression and improve exercise capacity and cardiopulmonary hemodynamics. Furthermore, oral administration may be the common preference for patients with FC I–II. Although some drugs have yielded side effects (48), the symptoms are often mild and eventually clear without treatment. In 2015, the outcomes of a meta-analysis demonstrated that the oral administration of PAH-specific drugs is a safe and effective treatment. However, this study incorporated sitaxsentan and imatinib, which are no longer in clinical use. Meanwhile, there is no detailed description of the precise treatment of PAH patients of different ages and FC grades with oral drugs.

Prostanoids, ERAs, and NO signaling pathway drugs are all used to achieve therapeutic goals through vasodilation, while RTK drugs can theoretically treat PAH by inhibiting the pathogenesis pathway of PAH, but their drug imatinib is not approved for the treatment of PAH due to side effects, such as subdural hemorrhage. Therefore, the three major classical pathway drugs are still mainly used clinically to treat PAH, and these traditional methods still have a high mortality rate, although they alleviate the symptoms to some extent. Nanomedicines and gene therapy are emerging approaches for the treatment of PAH in the future, but a higher level of evidence is needed to reach the goal of individualized treatment (49). In the meta-regression analysis, there is a correlation between CWEs and the change in 6MWD (p = 0.032; Figure 3), which possibly emphasizes the need to monitor CWEs.

Most NO drugs (including tadalafil, vardenafil, and riociguat) were identified to be effective. Indeed, Galie et al. (30), Vizza et al. (36), and Chang et al. (37) have found that oral udenafil and sildenafil might not improve the exercise capacity or pulmonary vascular remodeling in short-term treatment. Even treprostinil, a type of prostanoids, was detected as the only agent with a significant amelioration in exercise capacity, where it showed an obvious change in hemodynamics of prostanoids. AEs reported in the three classical methods were mild to moderate, with a high prevalence of headache. Additionally, the most common severe adverse drug response in oral ERAs was right-sided heart failure, accounting for approximately 14.0% (95% CI, range: 10.9–17.1%), dyspnea in the NO pathway (approximately 5.7%, 95% CI, range: 4.2–7.2%), and prostanoids (16.0%, 95% CI, range: 13.3–18.6%), respectively.

Age-treatment subgroup analysis indicated that the oral administration of NO pathway agents improved exercise capacity, cardiopulmonary hemodynamics, and worsening events-free survival rate across all age groups (<50 years and ≥50 years). In the younger populations (<50 years), NO revealed a significant improvement in 6MWD (MD = 38.37, p < 0.001) and a reduction of 0.50 in the OR of CWEs (p = 0.14). Additionally, the data of NO demonstrated excellent clinical efficacy in the older patients, increasing 6MWD by 28.20 m (p < 0.001), and significantly reducing CWEs, with an OR of 0.45 (p < 0.001). Age-related vasculature alteration is an obvious risk factor for PAH (50). Furthermore, clinical registries (51) have mentioned age-related differences in functional status and hemodynamics in PAH where the mean age of patients was reported as 50–65 years old. The Scottish composite index constructed a multivariate Cox model based on data from 182 PAH patients, using age, sex, etiology, right atrial pressure, cardiac output, and 6MWD to predict survival (52). Yi et al. found that older patients (≥50 years) were more likely to die than younger patients (<50 years) based on PAH registries in the United Kingdom and Ireland (48). This means that age is a predominant factor affecting patient prognosis. ERAs and NO significantly reduced the OR of CWEs by 53% (p = 0.02) and 54% (p < 0.001), respectively. ERAs showed the greatest efficacy on CWEs and could be used as the first targeted oral agent in elderly patients (≥50 years). Additionally, PAH is mainly a disease in women, according to data from registries (53). The study did not perform a subgroup analysis of sex and PAH classification because most of the 23 studies included women, and most of the patients had primary PAH.

In the subgroup analysis, subdivided by FC, ERAs demonstrated superior clinical efficacy in patients with FC I–II, 6MWD increasing by 19.74 m and reducing the OR of CWEs by 52%. ERAs also showed the best clinical efficacy compared to that of placebo in patients with FC III–IV, with a 6MWD 28.88-m improvement and a 53% reduction in the OR of CWEs. Although FC was not included in the Cox model mentioned above, FC and age were also included in the prognostic prediction as relevant parameters in some prediction equations or models proposed (54). By subgroup analysis of age and FC, patients were stratified using evidence-based medicine to aid doctors in choosing more appropriate drugs to improve patient outcomes.

Currently, patients with pulmonary hypertension are clinically classified into the following five groups: (1) those with predominantly pulmonary artery disease; (2) those consisting of pulmonary hypertension associated with left heart disease; (3) those with PAH associated with pulmonary disease and hypoxia; (4) those with PAH due to chronic thromboembolism; and (5) those due to unclear multifactorial mechanisms. This classification is widely accepted and used in clinical practice, but this approach is not ideal for some patients. Precision therapy, which can also be referred to as stratified therapy, intervenes based on the greatest benefit and least harm for most patients (55). We build on this by again subgrouping patients using age and FC class, narrowing the patient population so that the majority of patients in the group are susceptible to the drugs used, and improving prognosis. The NO drugs showed excellent efficacy in all age groups, but not in patients with FC I–II. However, in the subgroup analysis of FC, ERAs showed the best clinical efficacy. In clinical practice, doctors can choose the corresponding treatment plan based on basic patient information. First, we determine the age of the patient and select the appropriate drug. Then, consider the FC grade of the patient and decide whether to add other drugs to form a dual or triple treatment. In general, the clinical conditions of patients taking oral drugs are not serious, which is why most of the patients involved in this study were in FC II–III. When the patient does not fall under any of these conditions, other treatments can be used, such as inhaled or intravenous drugs. When the level of individualized treatment is not reached, age and FC grade can be first subdivided into a small number of patients to achieve accurate treatment for this small population.

The limitations of this study are as follows: (1) the sample size of some studies was too small and there was great uncertainty; (2) only studies in English were included in this meta-analysis, and studies not included in other languages may result in partial data omission; (3) since this was a secondary study, it was difficult to obtain individual patient data, which may cause uncertainty in the data; (4) only some studies have reported hemodynamic changes; and (5) fewer studies were pooled in the subgroup analysis.

In this meta-analysis, we assessed the efficacy and safety of orally targeted drugs for PAH. This study compared the clinical efficacy of three classical oral targeted drugs through subgroup analysis of age and FC grade, providing evidence-based medicine for precise clinical treatment.

The original contributions presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

H-RZ and QL collected the data. H-RZ and H-YK analyzed the data. H-RZ wrote the manuscript. H-YK modified the manuscript. X-JJ provided the idea. All authors contributed to the article and approved the submitted version.