Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study

Abstract

IntroductionPulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). We sought to quantify survival and determine factors predictive of mortality in a cohort of patients with CTD-associated PAH (CTD-PAH) in the current era of advanced PAH therapy.MethodsPatients with right heart catheter proven CTD-PAH were recruited from six specialised PAH treatment centres across Australia and followed prospectively. Using survival methods including Cox proportional hazards regression, we modelled for all-cause mortality. Independent variables included demographic, clinical and hemodynamic data.ResultsAmong 117 patients (104 (94.9%) with systemic sclerosis), during 2.6 ± 1.8 (mean ± SD) years of follow-up from PAH diagnosis, there were 32 (27.4%) deaths. One-, two- and three-year survivals were 94%, 89% and 73%, respectively. In multiple regression analysis, higher mean right atrial pressure (mRAP) at diagnosis (hazard ratio (HR) = 1.13, 95% CI: 1.04 to 1.24, P = 0.007), lower baseline six-minute walk distance (HR = 0.64, 95% CI: 0.43 to 0.97, P = 0.04), higher baseline World Health Organization functional class (HR = 3.42, 95% CI: 1.25 to 9.36, P = 0.04) and presence of a pericardial effusion (HR = 3.39, 95% CI: 1.07 to 10.68, P = 0.04) were predictive of mortality. Warfarin (HR = 0.20, 95% CI: 0.05 to 0.78, P = 0.02) and combination PAH therapy (HR = 0.20, 95% CI: 0.05 to 0.83, P = 0.03) were protective.ConclusionsIn this cohort of CTD-PAH patients, three-year survival was 73%. Independent therapeutic predictors of survival included warfarin and combination PAH therapy. Our findings suggest that anticoagulation and combination PAH therapy may improve survival in CTD-PAH. This observation merits further evaluation in randomised controlled trials.

Should patients with systemic sclerosis‐related pulmonary arterial hypertension be anticoagulated?

“…1). 8 With a hazard ratio of 0.20 (95% CI: 0.05-0.78, P = 0.02), we found an estimated fivefold reduction in mortality with anticoagulation over mean (standard deviation) 2.6 (1.8) years. In multivariable proportional hazards regression analysis, this benefit was present even after adjusting for the severity of PAH (based on World Health Organisation functional class, baseline mean right-atrial pressure (mRAP) and 6-min walk distance (6MWD)), and concomitant advanced PAH-specific therapy (including combination therapy with more than one drug).…”

“…6,7 In the Australian Scleroderma Cohort Study (ASCS), despite treatment with PAH-specific therapies, the median survival following right-heart-catheter diagnosis of PAH is only 5 years. 8 This is comparable to many forms of advanced malignancy. Furthermore, patients with SSc-PAH often require multiple hospital admissions and frequently use other healthcare resources, including emergency departments and clinics.…”

“…26 In our Australian cohort study, while physicians at some centres favoured anticoagulation, the frequency of use of warfarin was generally around 30%, with none of the centres 'routinely' anticoagulating patients with SSc-PAH. 8 …”

“…Observational studies evaluating a role for anticoagulation in PAH, with mortality as an end point, are summarised in Table 1. 8,[13][14][15][16][18][19][20][21] While the findings of these observational studies are important for generating hypotheses regarding potential benefits of therapies, such studies may be biased because of non-random allocation of treatment and 'confounding by indication'.…”

Letter by Nikpour et al Regarding Article, “Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL)”

“…Although in the Discussion the authors refer to 8 previous observational studies evaluating the role of anticoagulation in PAH, we note that a key reference by Ngian et al 3 was omitted from the article itself and its accompanying editorial. Because this is 1 of only 4 observational studies (including REVEAL) to evaluate the role of anticoagulation with warfarin in systemic sclerosis PAH (n=104; of whom 30% were anticoagulated) and the only study to show a survival benefit (multivariable hazard ratio for mortality, 0.20; 95% confidence interval, 0.05-0.78, P=0.02), even after adjustment for PAH severity and concomitant advanced PAH therapy, we believe that its inclusion is important in presenting a more balanced discussion of this contentious area.…”