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

Am J Respir Crit Care Med. 2021 Feb 15;203(4):484-492. doi: 10.1164/rccm.202004-1006OC.


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 + 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.

Keywords: echocardiography; pulmonary arterial hypertension; pulmonary vascular resistance; right heart remodeling; upfront therapy.

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Antihypertensive Agents / therapeutic use*
  • Drug Combinations
  • Endothelin Receptor Antagonists / administration & dosage
  • Endothelin Receptor Antagonists / therapeutic use*
  • Female
  • Hemodynamics / drug effects*
  • Humans
  • Male
  • Middle Aged
  • Phosphodiesterase 5 Inhibitors / administration & dosage
  • Phosphodiesterase 5 Inhibitors / therapeutic use*
  • Pulmonary Arterial Hypertension / diagnosis*
  • Pulmonary Arterial Hypertension / drug therapy*
  • Risk Reduction Behavior
  • Treatment Outcome
  • Vascular Resistance / drug effects*


  • Antihypertensive Agents
  • Drug Combinations
  • Endothelin Receptor Antagonists
  • Phosphodiesterase 5 Inhibitors