Effect of Warfarin on Survival in Pulmonary Arterial Hypertension
What is the effect of warfarin anticoagulation on survival in idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with systemic sclerosis (SSc-PAH) patients enrolled in REVEAL, a longitudinal registry of Group I PAH?
Patients who initiated warfarin (n = 187) were matched 1:1 with patients never on warfarin. Descriptive analyses were used to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from time of warfarin initiation or a corresponding quarterly update in matched pairs. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH).
Mean age was 51 years in IPAH (n = 288) and 63years in SSc-PAH (n = 86), and >80% were female. Two-thirds of patients initiating warfarin discontinued treatment prior to last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio [HR], 1.37; p = 0.21) or in SSc-PAH patients (adjusted HR, 1.60; p = 0.15) compared with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (HR, 1.57; p = 0.031) or any time post baseline (HR, 1.49; p = 0.046) had increased mortality compared with warfarin-naïve patients.
No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than inpatients not receiving warfarin, even after adjusting for confounders.
Warfarin has been recommended in IPAH and SSc-PAH primarily because of the small vessel thrombi thought to contribute to the pathogenesis. The demonstration of an increased mortality in SSc-PAH in this study is based on a small matched cohort, but in the absence of a controlled trial appears adequate to avoid warfarin. While there was no benefit to warfarin in IPAH (288 patients) in the REVEAL registry, it was effective in the European prospective registry of 800 patients with IPAH of whom 66% were treated with anticoagulants (Circulation, 2014). In IPAH, there was a significantly better 3-year survival (p = 0.006) (Cox multivariable regression analysis HR, 0.79) compared with patients who never received anticoagulation. The survival difference at 3 years remained statistically significant (p = 0.017) in a matched-pair analysis of 336 IPAH patients. In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH including connective tissue and congenital heart disease.
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