Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension

Abstract

Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known.Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs. Methods:The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist 1 phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores.Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR ,25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status.Conclusions: A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.

The Growing Role of Echocardiography in Pulmonary Arterial Hypertension Risk Stratification: The Missing Piece

“…Double oral therapy showed an additional effect on PVR reduction compared with oral monotherapy, with a reduction ranging between 30 and 60% [19,[62][63][64]. Such modest improvement in PVR, usually <50% for the majority of patients treated with double oral therapy, is associated with a non-significative improvement in echo-determined right heart sizes, while weakly associated with improvement in RV systolic function [60].…”

“…Such RHRR is associated with excellent long-term survival and quality of life. However, studies showed that monotherapy or stepwise additions to initial monotherapy allow these results in a small percentage of patients (18%) [56,61,63,67]. On the other hand, an upfront combination therapy, including parenteral prostacyclins, is associated with RHRR in a greater proportion of patients than other treatment strategies as a function of PVR reduction.…”

Reply to Weatherald et al.: Pulmonary Vascular Resistance in Pulmonary Arterial Hypertension: La Pièce de Résistance?

“…We thank Weatherald and colleagues for their supportive comments, and pleasant reminiscence of French cuisine, on our recent report on risk reduction and hemodynamics after initial dual combination of therapies in pulmonary arterial hypertension ( 1 ). We fully agree on the importance of pulmonary vascular resistance combined with imaging of the right heart, as there may be dissociation ( 2 ), although this is unlikely when pulmonary vascular resistance decreases by more than 50–60% ( 3 ).…”

Pulmonary Vascular Resistance in Pulmonary Arterial Hypertension: La Pièce de Résistance?

“…We read the recent manuscript by Badagliacca and colleagues with great interest ( 1 ). In this Italian multicenter retrospective cohort of 181 treatment-naive patients with pulmonary arterial hypertension (PAH), they evaluated the relationship between change in pulmonary vascular resistance (PVR) following initiation of dual oral combination therapy and two widely used approaches for multidimensional risk assessment ( 2 , 3 ).…”

“…Lastly, Badagliacca and colleagues highlight the near certainty of treatment failure with dual oral combination therapy in high-risk patients, as none improved to low risk in their study ( 1 ). This reinforces the notion of initial triple combination therapy, including a parenteral prostacyclin for high-risk patients, consistent with previous observational studies ( 9 , 10 ) and the treatment algorithm proposed in the sixth World Symposium on Pulmonary Hypertension ( 11 ).…”