Methods

This prospective cohort study comprised 280 consecutive patients ≥18 years of age with IPAH at 2 national referral centers in China from January 2007 to July 2012. IPAH was defined according to the current guidelines, including right-sided cardiac catheterization demonstrating a mean pulmonary artery pressure ≥25 mm Hg and a mean pulmonary arterial capillary pressure ≤15 mm Hg at rest. Patients who were in sinus rhythm at baseline met the criteria for inclusion. We excluded patients with other types of pulmonary hypertension, as well as acute vasodilator responders, patients with preexisting SVA or other types of arrhythmias, patients with enlarged left atria and/or left-sided cardiac disease, and patients with implanted cardiac pacemakers.

Baseline demographics, World Health Organization (WHO) functional class, 6-minute walk distance according to the recommendations of the American Thoracic Society, and hemodynamics by right-sided cardiac catheterization were collected before enrollment. Baseline echocardiography and electrocardiography were performed in all patients. Follow-up visits were regularly performed in the outpatient clinic or hospital every 3 to 6 months, or when clinically indicated. Data on clinical manifestation, WHO functional class, 6-minute walk distance, B-type natriuretic peptide, electrocardiography, and treatment were recorded at each visit. Follow-up echocardiography and right-sided cardiac catheterizations were done as clinically indicated.

The primary outcome was all-cause mortality. Patients was followed until April 30, 2013, and those lost to follow-up were censored as alive on the last day of contact. On the basis of the presence of SVA during the follow-up period, patients were divided into 2 groups: (1) patients who developed SVA and (2) patients who did not develop SVA. Subgroup analysis was performed in patients with permanent and transient SVA and in those who never experienced SVA. The study was performed according to good clinical practice and in compliance with the Declaration of Helsinki. Informed consent was obtained from every patient, which was carried out with the permission of the local institutional ethics committees.

SVA were specified to include sustained atrial fibrillation, atrial flutter, or atrial tachycardia detected on electrocardiography, requiring hospitalization or intervention. The diagnosis of SVA was confirmed by 2 cardiologists in the diagnosis and management of cardiovascular disease. Atrial fibrillation was defined by the replacement of consistent P waves by rapid oscillations or fibrillatory waves and an irregular ventricular response. Atrial flutter was characterized by an organized atrial rhythm with a rate of 250 to 350 beats/min and a sawtooth-like pattern in leads II, III, and aVF. Atrial tachycardia was usually manifest by atrial rates of 100 to 250 beats/min, rarely at 300 beats/min. The P wave occurs in the second half of the tachycardia cycle and is frequently obscured by the T wave of the preceding QRS complex.

The rhythm-control strategy attempts restoration and maintenance of sinus rhythm for patients with SVA. For the purpose of this study, sinus rhythm was considered stable when it was maintained for most parts of the follow-up period and when it was still present at the end of the study. According to the guidelines, medical therapy for atrial tachycardia consisted of amiodarone. An attempt at catheter ablation was considered for patients with recurrent symptomatic atrial tachycardia. The strategy for atrial flutter was to restore sinus rhythm with direct-current electrical cardioversion with energies <50 J by using monophasic shocks, atrial overdrive pacing, and/or antiarrhythmic drug therapy (preferably with amiodarone). Rate control is especially important if conversion to sinus rhythm is deferred or patients present with 2-to-1 or higher grades of atrioventricular block. Anticoagulant therapy is deemed important before any mode of cardioversion for those with atrial flutter of >48 hours in duration. Clinically stable patients with atrial fibrillation were treated with amiodarone for cardioversion and prevention of recurrence after successful restoration of sinus rhythm (intravenous administration of amiodarone 5 mg/kg over 30 minutes, then 1.2 to 1.8 g/day and oral doses until 10 g total, then 200 mg/day maintenance). In patients in whom sinus rhythm could not be restored, digoxin was used for rate control (0.125 mg/day orally), if deemed appropriate. Antithrombotic therapy to prevent thromboembolism is recommended for all patients with atrial fibrillation, except those with lone atrial fibrillation or contraindications.

Data are presented as numbers, percentages, or mean ± SD. Baseline characteristics of patients who did develop SVA were compared with those of patients without SVA by unpaired Student’s t or Mann-Whitney U tests, as appropriate. Pearson’s chi-square or Fisher’s exact tests were used for categorical variables. Univariate Cox proportional regression analysis was performed to identify risk factors for SVA and death. Other variables believed to have clinical importance and those with p values <0.05 in the univariate analysis were considered as confounders. Using a forward stepwise multivariate model, the risk factors for SVA and mortality were analyzed by adjusting for other possible factors. Results of the analysis are presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Kaplan-Meier survival curves was used to estimate the cumulative incidence of SVA, survival of patients who did and did not develop SVA (for this analysis, only the first SVA event was counted), and survival of patients with permanent and transient SVA and those who never experienced SVA. A p value <0.05 was considered significant. Statistical analysis was performed using SPSS version 17.0 (SPSS, Inc., Chicago, Illinois).