Treatment of Pulmonary Hypertension: Is Triple Therapy Necessarily Better than Monotherapy?

To the Editor:

Recently, Boucly and colleagues (1) found that long-term survival was independently related to the initial treatment strategy in a large cohort of patients newly diagnosed with idiopathic, hereditary, or anorexin-induced pulmonary arterial hypertension (PAH). Initial triple therapy treatment, including parenteral prostacyclin, was associated with a better overall survival rate than monotherapy or dual therapy with or without parenteral prostacyclin. The authors further clarified the relationship between the initial treatment strategy and long-term survival rate in patients with PAH, providing a new basis for its treatment. However, this relationship has not been fully studied so far.

PAH is a life-threatening disease, and the median survival time of untreated adult patients is less than 3 years (2). It can be seen that the initial treatment strategy for PAH is vitally important. Studies have found that triple therapy for PAH reduced the risk and reversed right heart remodeling (3). In several randomized controlled trials and meta-analyses, it was proven that a combination of different approaches could improve hemodynamics, clinical function, and survival time (4). However, Stubbe and colleagues (5) showed that the 12-month survival rates of “atypical” and “typical” patients with PAH were similar. In the “atypical” PAH group, there was no difference in the 12-month survival rate between triple therapy patients and monotherapy patients. Therefore, there is still a little controversy about the prognosis of PAH between triple therapy and monotherapy.

In the study by Boucly and colleagues (1), the authors made comparisons after matching age, sex, and pulmonary vascular resistance to correct these confounding factors. However, compared with younger patients with PAH, those over 65 years of age had lower enthusiasm for being prescribed targeted PAH drugs, affecting the survival rate even after adjusting for age (5). In addition, other important prognostic variables such as echocardiography and cardiac magnetic resonance imaging were considered part of a comprehensive risk assessment strategy (6). However, the authors did not systematically collect or analyze them. Moreover, the authors did not compare the side effects caused by triple therapy and monotherapy. Although triple therapy improves the survival rate, the side effects of multiple drugs may further affect patients’ quality of life, so it is also necessary to assess the long-term impact of the side effects. Furthermore, triple therapy is more expensive than monotherapy, which will invisibly eliminate some low-income patients and may cause the selected population to be less representative. The price will also affect the promotion of subsequent treatments. Therefore, it is necessary for us to conduct various subgroup analyses to further compare the benefits and risks of triple therapy. In addition, the authors’ research is aimed at idiopathic PAH. However, there are many patients with secondary PAH in clinics, and whether the same results arise between triple therapy and monotherapy requires further verification. Finally, we suggest that the authors can further analyze the decision curve and clinical impact curve to evaluate the clinical efficacy of triple therapy and provide further proof. At present, there are few large-scale randomized controlled studies on triple therapy for PAH, and there is a lack of evidence in this regard. We look forward to conducting prospective multicenter randomized controlled studies to further evaluate the efficacy of initial triple therapy and monotherapy or double therapy.