Introduction

Pulmonary arterial hypertension (PAH), which comprises World Health Organization (WHO) Class I pulmonary hypertension (PH), is a challenging entity that affects 10-52 adults per million.¹ From a hemodynamic perspective, PAH is characterized by the presence of elevated mean pulmonary artery pressures >25 mm Hg in the setting of a normal pulmonary capillary wedge pressure <15 mm Hg. PAH can be idiopathic or may be associated with a variety of associated conditions, including congenital heart disease (CHD), viruses (e.g., HIV), connective tissue disorders, drugs/toxins, and hemoglobinopathies.² The etiology of PAH is thought to be a result of vascular constriction, cellular proliferation and, to some degree, a prothrombotic state.³ Idiopathic PAH (IPAH) has a well-characterized natural course, with median survival of two to three years,⁴ but this may be in flux as PH-targeted therapies are increasingly implemented. Specifically, the advent of modern medical therapies, including prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors has improved the prognosis of PAH; however, it remains a progressive, fatal disease. The background therapy for PAH includes diuretics and supplemental oxygen, but the suspected prothrombotic state in PAH also implicates a role for anticoagulation, of which only warfarin has been studied. However, the data regarding anticoagulation in PAH are equivocal and complicated by the heterogeneous PAH population. As such, there is much that is still unclear, especially in the setting of the evolving medical therapies for PAH. Moving forward, the role of anticoagulation will need to be better defined, especially with the increased utilization of non-vitamin K oral anticoagulants (NOACs).

Current Guidelines

The lack of convincing data in regards to the use of anticoagulation in PAH is clear from the discrepancy among the various guidelines. The ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension recommends warfarin anticoagulation with a goal international normalized ratio (INR) 1.5-2.5 in IPAH patients, citing one prospective and two retrospective non-controlled observational studies. The expert consensus concedes that "few data exist to guide recommendations for patients with associated forms of PAH," but "recommend anticoagulation in such patients with more advanced disease, such as those on continuous intravenous therapy."² While the 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension⁵ also recommend anticoagulation for this patient population, they suggest an INR goal of 2.0-3.0. The discrepancy and lack of strong recommendations reflect the lack of convincing data, despite a number of studies.

Data

Given the heterogeneity of the PAH population, as well as the limited sample size, there have been no randomized prospective studies of anticoagulation in these patients. Most of the data stems from single center retrospective cohorts, and no studies were done for the specific purpose of studying the role of anticoagulation. For example, there were four single center cohort studies performed to investigate this question between 1984 and 2002, and all but one demonstrated an improved survival amongst patients with IPAH treated with warfarin. Unfortunately, only one of those was a prospective study, all had a limited sample size, and none of them utilized contemporary PH-targeted drugs.^6-9 The first study that included PH-targeted drugs was performed in 2005, and was a retrospective cohort study that demonstrated an improved transplant-free survival associated with the use of warfarin.¹ This latter study was greatly undermined by a limited sample size, as it only included 66 patients with IPAH.

Two recent analyses of PAH registries highlight the equipoise regarding the role of anticoagulation in PAH. A 2014 analysis of the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) registry¹¹ utilized 1,283 consecutively enrolled patients with newly diagnosed PAH, and examined survival rates based on use of anticoagulation. In the subgroup of patients with IPAH, use of anticoagulation was associated with a statistically significant improved three-year survival, which held up in matched pair analysis. However, in patients with other forms of PAH (most commonly associated with connective tissue diseases (CTD), CHD, and portopulmonary hypertension), there was no survival benefit associated with anticoagulation. In contrast, a 2015 analysis of the Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) registry¹² compared patients newly started on warfarin (N=187) with matched controls who had never been treated with warfarin and studied survival in patients with IPAH and systemic sclerosis associated PAH. The findings of this study demonstrated no survival benefit associated with warfarin use amongst patients with IPAH, and actually demonstrated increased mortality associated with warfarin in the subgroup with systemic sclerosis. The major difference between these two recent studies was the fact that the COMPERA analysis included patients who were on warfarin at time of study initiation, while those included in the REVEAL analysis were newly started on warfarin.

Conclusion

The diagnosis and management of PAH has evolved dramatically with the advent of directed therapies, and this has resulted in an increased life expectancy for those with the condition. If the advances continue and PAH evolves into a more chronic illness, the importance of background therapies is magnified. The current data suggest that anticoagulation likely does not benefit patients with CTD-associated PAH, but is equivocal amongst those with IPAH. Another important consideration going forward is that anticoagulants themselves are rapidly evolving. A number of studies have demonstrated that NOACs are at least as effective as warfarin in the management of venous thromboembolism and atrial fibrillation, and several studies have demonstrated reductions in bleeding and mortality.

Given the distinct mechanisms of IPAH, it is dangerous to extrapolate these data, but they provide a potentially promising avenue for future research. One recent study¹³ of a monocrotaline-induced PAH rat model investigated the role of rivaroxaban in mitigating the adverse effects of PAH. Specifically, the study found that rivaroxaban, in a dose-dependent fashion, attenuated the increase in right ventricular systolic pressure and right ventricular hypertrophy caused by monocrotaline. Although there are limitations to the monocrotaline model of PH, the findings do warrant further investigation into the role of NOACs in PAH management. The void of convincing evidence regarding the role of anticoagulation in PAH is humbling, but provides tremendous potential for future research endeavors. At this time, anticoagulation for the management of PAH remains a patient-specific decision that has to be weighed carefully by any provider.

References

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Keywords: Anticoagulants, Atrial Fibrillation, Blood Pressure, Cell Proliferation, Chronic Disease, Consensus, Constriction, Disease Management, Diuretics, Endothelin Receptor Antagonists, HIV Infections, Hemoglobinopathies, Hypertension, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, International Normalized Ratio, Matched-Pair Analysis, Monocrotaline, Oxygen, Phosphodiesterase Inhibitors, Prognosis, Prospective Studies, Pulmonary Artery, Pulmonary Wedge Pressure, Scleroderma, Systemic, Survival Rate, Venous Thromboembolism, Viruses, Vitamin K, Warfarin

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