Electrocardiographic Abnormalities and Their Association with Outcomes in Randomized Clinical Trials of Pulmonary Arterial Hypertension.

Rationale PAH is a progressive disease with manifestations including right atrial enlargement, right ventricular dysfunction, dilation and hypertrophy. ECG is a non-invasive, inexpensive test that is routinely performed in clinical settings. Prior studies have described separate abnormal findings in ECGs of patients with PAH. However, the role of composite ECG findings reflective of right heart disease for risk stratification, clinical trial enrichment and management of patients with PAH has not been explored. Objectives i. Describe a pattern of right heart disease on ECG in patients with PAH. ii. Investigate the association of this pattern with clinical measures of disease severity and outcomes. Methods We harmonized individual participant data from 18 Phase-III randomized clinical trials of therapies for PAH (1998 - 2013) submitted to the FDA. Right heart disease (RHD) was defined as the presence of RV hypertrophy, right axis deviation, right atrial enlargement, or right bundle branch block on ECG. Random effects linear regression, multilevel ordinal regression (cumulative link model), and Cox proportional hazards models were used to assess the association of RHD by ECG with six-minute walk distance (6MWD), WHO functional class, and clinical worsening after a priori adjustment for age, sex, body mass index and PAH etiology. Effect modification of treatment and ECG abnormalities was assessed by including an interaction term. Results 4439 patients had baseline ECGs and 68% patients had evidence of RHD. RHD on ECG was associated with higher PVR (p<0.001) and higher mean PA pressures (p<0.001). Patients with RHD on ECG had 10 meters shorter 6MWD (p=0.005) and worse WHO functional class (p<0.001) at baseline. RHD on baseline ECG was associated with increased risk of clinical worsening (HR=1.42, 95%CI=1.21,1.67, p<0.001). Patients with RHD had greater treatment effect in terms of 6MWD, WHO-FC and time to clinical worsening compared to those without (p for interaction= 0.03, 0.001 and 0.03, respectively). Conclusion Right heart disease by ECG may be associated with a worse outcomes and potentially greater treatment effect. ECGs could be an inexpensive, widely available noninvasive method to enrich clinical trial populations in PAH.