|Year : 2017 | Volume
| Issue : 4 | Page : 108-111
The role of oral anticoagulation therapy in pulmonary arterial hypertension
Eleni Vrigkou M.Sc. 1, Argyrios Tsantes2, Athanasios Pappas1, Iraklis Tsangaris1
1 Second Department of Critical Care Medicine, Attiko University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
2 Laboratory of Hematology & Blood Bank Unit, Attiko University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
|Date of Web Publication||18-Jan-2018|
Second Department of Critical Care Medicine, Attiko University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens
Source of Support: None, Conflict of Interest: None
Pulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by increased pulmonary vascular resistance and right-sided heart failure. Despite the advances in PAH medical treatment, morbidity and mortality rates remain high. Oral anticoagulants are part of the supporting PAH treatment scheme, even though their use is based mainly on non-controlled, single-centered observational studies. The conflicting current research, the potential side effects of the anticoagulation treatment and the ambiguity of the European Society of Cardiology and European Respiratory Society pulmonary hypertension guidelines have raised concerns regarding the implementation of this intervention and heterogeneity in its application in every day clinical practice. A careful selection of the patient subgroups that oral anticoagulation therapy could be beneficial, a consideration of individual patient characteristics and a close monitoring of the anticoagulation treatment could be of importance in order to limit clinician’s concerns and minimize any potential side effects.
Keywords: oral anticoagulants; warfarin; pulmonary arterial hypertension
|How to cite this article:|
Vrigkou E, Tsantes A, Pappas A, Tsangaris I. The role of oral anticoagulation therapy in pulmonary arterial hypertension. Clin Trials Degener Dis 2017;2:108-11
|How to cite this URL:|
Vrigkou E, Tsantes A, Pappas A, Tsangaris I. The role of oral anticoagulation therapy in pulmonary arterial hypertension. Clin Trials Degener Dis [serial online] 2017 [cited 2021 Mar 7];2:108-11. Available from: https://www.clinicaltdd.com/text.asp?2017/2/4/108/222183
| Introduction|| |
Pulmonary arterial hypertension (PAH) is a severe, progressive disease characterized by pathologic alterations to the anatomical and molecular structure of the pulmonary vasculature, resulting in increased pulmonary vascular resistance and right-sided heart failure. Since the early 2000s, treatment options for PAH patients are based on agents targeting the prostaglandin, endothelin and nitric oxide pathways. Even though the advanced PAH therapies have dramatically improved survival, morbidity and mortality rates remain high. For several decades, oral anticoagulants have been used as supportive treatment in PAH. The rationale behind this recommendation is quite solid, even though it is acknowledged that it is based mainly on non-controlled, single-centered observational studies, while current literature is controversial. The lack of sufficient data on the subject is reflected in the current European Society of Cardiology and European Respiratory Society (ESC/ERS) pulmonary hypertension guidelines. The conflicting current research, the potential side effects of the anticoagulation treatment and the ambiguity of the ESC/ERS guidelines have raised concerns regarding the implementation of this intervention and heterogeneity in its application in every day clinical practice.
| Current Practice|| |
PAH is a complex disease, whose multifactorial etiopathology is the basis for its classification in 4 groups: idiopathic (IPAH) and heritable PAH (HPAH), PAH associated to drugs and toxins and associated forms of PAH that localize to small pulmonary muscular arterioles (like connective tissue disease (CTD), human immunodeficiency virus infection, portal hypertension, congenital heart disease and schistosomiasis). Advanced PAH medical therapy includes three major categories: endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostacyclin analogues. Oral anticoagulants are a part of the background medical therapy, along with oxygen, diuretics and calcium channel blockers.
The ESC/ERS pulmonary hypertension guidelines state that “oral anticoagulant treatment may be considered in patients with IPAH, HPAH and PAH due to use of anorexigens” (recommendation class IIb/level C). Oral anticoagulants may also be considered in cases of CTD-PAH and PAH associated with congenital heart disease in cases of thrombophilic predisposition, signs of thrombosis or heart failure in the absence of contradictions (recommendation class IIb/level C). Regarding the other forms of PAH, there are insufficient data for a recommendation to be made, apart from porto-pulmonary hypertension where anticoagulation is not recommended due to the increased bleeding risk. The oral anticoagulant of choice is warfarin.
| PAH Pathophysiology and Oral Anticoagulants|| |
Even though the etiology behind PAH is variable and its pathophysiology is complex and still elusive, the hallmarks of the disease justify the introduction of oral anticoagulants in the PAH treatment scheme. PAH is a proliferative vasculopathy, where endothelial dysfunction, pathologic remodeling, vasoconstriction and an imbalance in vasoactive mediators (favoring vasoconstrictors and pro-proliferative mediators and decreasing vasodilators) play a central role in its pathophysiology. The addition of oral anticoagulants as supportive treatment in PAH was brought by the results of several observational studies demonstrating evidence of vascular thrombotic lesions and in situ thrombosis in the small caliber peripheral pulmonary vessels in post-mortem evaluations. The value of those classic studies is immense regarding the understanding of the pathophysiological background of the disease. Nevertheless, it should be acknowledged that they were conducted in the 80s and 90s, they involved mainly IPAH and CTD-PAH patients and they did not demonstrate a causative role between those findings and the disease. Moreover, they stated that fresh platelet-fibrin thrombi and organized arterial thrombi were infrequent in the tested specimens.
Recent studies regarding the coagulation status of PAH patients are conflicting. Current data of dysregulation of the coagulation process and impaired fibrinolysis have suggested a possible prothrombotic state and supported the use of oral anticoagulation in PAH. Interestingly, a number of studies assessing the levels of circulating markers of thrombogenesis and fibrinolysis (namely plasminogen activator inhibitor-1, thrombin-antithrombin, prothrombin fragments 1+2) have rendered inconsistent results, leaving unanswered questions about the role of the observed coagulation abnormalities in the disease’s natural history.
As the coagulation cascade is a complex and fast-changing dynamic equilibrium and PAH is a progressive, chronic disease, the nature of the coagulation deficits observed in the PAH setting could be associated to variable factors, such as the etiology of PAH or the severity, trajectory and duration of the disease, rendering difficult for conclusions to be made about the coagulation profile of the patients (especially in cases were a thrombophilic predisposition is lacking). Moreover, the frequently detected and still of unknown etiology thrombocytopenia observed in the PAH population could play a significant part in the disease’s hemostatic state, even more so since it has been correlated with the disease’s prognosis.
| The PAH Patient and Oral Anticoagulants|| |
Since immobility, venous congestion, sluggish pulmonary blood flow and right-sided heart failure are parts of PAH’s clinical presentation, anticoagulation treatment is a logical option. Furthermore, PAH patients often present with prothrombotic conditions and increased risk of catheter-associated thrombosis (in cases receiving intravenous prostanoids). A thrombus formation or an embolism could result in the hemodynamical destabilization of the patients with serious consequences, strengthening the importance of anticoagulation therapy.
With the change of the PAH population’s demographics, more and more patients with advanced age and serious concomitant conditions (like liver or kidney failure) are being diagnosed with the disease. PAH patient’s bleeding risk can also be augmented by conditions like hemoptysis, gastrointestinal disease, esophageal varices and liver dysfunction frequently presented in that population.
Studies conducted to make a risk-benefit analyses on the use of anticoagulants in PAH patients are scarcer than those conducted to determine the effect of anticoagulation treatment on survival. Although the latter are controversial, the former show an increased risk of bleeding in the CTD-PAH and IPAH population, but are still unconfirmed by larger, controlled studies. An additional concern is that in cases PAH patients are prescribed oral anticoagulants, there are no guidelines on their anticoagulation management or even a consensus for the target international normalized ratio (INR) range.
The ‘advanced’ PAH therapies have greatly improved survival and they are used as monotherapy or (more often in our days) combination therapy according to the risk stratification. Some of those medications have a direct effect on the coagulation process (like prostacyclin analogues that inhibit platelet aggregation and are associated with thrombocytopenia), while others have an indirect effect (through, for example, the NO pathway). Moreover, endothelin-receptor antagonists and sildenafil interfere with the metabolism of vitamin K antagonists and bosentan decreases warfarin’s anticoagulant effects. To date, there are no reliable data evaluating the risks and benefits of concomitant prescription of oral anticoagulants and advanced PAH therapies.
The most frequent anticoagulant used in the PAH setting is warfarin. Warfarin presents with several problems regarding its use, like the non-fixed dose regime, the continuous need for monitoring, the non-reliable anticoagulant effect, the interactions with diet and the increased bleeding complications. Limited data are available regarding the use of alternative coagulation treatment to warfarin, like the new oral anticoagulants (NOACs) or antiplatelet agents. NOACs could have some advantages over warfarin, mainly due to their easier management and fewer bleeding complications. Even though preliminary data from experimental models are encouraging, larger studies are warranted in order to fully assess their role in the PAH treatment scheme.
| Discussion|| |
There is considerable uncertainty regarding the use of anticoagulation in PAH patients. The conflicting data from observational studies and the lack of randomized controlled trials have raised concerns about the prescription of oral anticoagulants in every day clinical practice. Two of the most important studies in the field, the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and the Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) have rendered respective results concerning CTD-PAH, but not IPAH patients: they did not demonstrate a positive effect of the anticoagulation therapy on survival in CTD-PAH, but while COMPERA showed a beneficial impact in IPAH, the REVEAL registry did not.
The most important question that needs to be answered for a definite decision to be made regarding anticoagulants in PAH is whether in situ thrombosis or thromboemboli may have an important impact in the disease’s natural history and if so, which of the patients present with increased risk of thrombosis. It is well known that the pathophysiological background of the disease is, for a great part, still elusive. It has not been yet established if thrombosis is a cause, a consequence or merely a finding with no particular significance to the diseases progression.
Nonetheless blood coagulation abnormalities have been observed in PAH along with evidence of in situ thrombosis (especially in the IPAH population). Those findings suggest that at least a subgroup of PAH patients may benefit from oral anticoagulants, since their disease could be complicated by thrombosis or thromboembolism. In order to detect those hidden patients, periodically conducted ventilation/perfusion lung scans or CT angiograms could be of use.
In patients at a greater risk of thromboemboli due to lower cardiac output, higher pulmonary vascular resistance, progressive right ventricle failure, immobility or thrombophilia, anticoagulation is a vital option. Even though there are no definite guidelines regarding anticoagulation management in those cases, a close monitoring of the anticoagulation treatment (by regular blood works, INR tests and clinical examinations) could be of importance.
Anticoagulation therapy could be considered based on case-by-case evaluation. The etiology of the disease should be an important factor towards making that decision: CTD-PAH patients have an increased bleeding risk, patients with congenital heart disease often present with hemoptysis and in porto-pulmonary hypertension anticoagulants are contradicted due to hemorrhage complications. Individual patient characteristics should also be taken under consideration, such as the severity and trajectory of the disease, prior bleeding history, concomitant clinical conditions and medications.
PAH is a severe, complex disease, whose treatment can be influenced by various factors. Anticoagulation treatment is a part of the PAH treatment scheme for some patient subgroups, but is recently subjected to scrutiny due to the conflicting data regarding its beneficial impact on survival and its potential side effects. A careful consideration of individual patient characteristics and a close monitoring of the anticoagulation treatment could be of importance in order to minimize any potential side effects.
| References|| |
Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol
Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J
Montani D, Günther S, Dorfmüller P, et al. Pulmonary arterial hypertension. Orphanet J Rare Dis
Ezedunukwe IR, Enuh H, Nfonoyim J, Enuh CU. Anticoagulation therapy versus placebo for pulmonary hypertension. Cochrane Database Syst Rev
Roldan T, Landzberg MJ, Deicicchi DJ, Atay JK, Waxman AB. Anticoagulation in patients with pulmonary arterial hypertension: An update on current knowledge. J Heart Lung Transplant
Robinson JC, Pugliese SC, Fox DL, Badesch DB. Anticoagulation in Pulmonary Arterial Hypertension. Curr Hypertens Rep
Mojadidi MK, Goodman-Meza D, Eshtehardi P, et al. Thrombocytopenia is an independent predictor of mortality in pulmonary hypertension. Heart Lung
Caldeira D, Loureiro MJ, Costa J, Pinto FJ, Ferreira JJ. Oral anticoagulation for pulmonary arterial hypertension: systematic review and meta-analysis. Can J Cardiol
Henkens IR, Hazenoot T, Boonstra A, Huisman MV, Vonk-Noor degraaf A. Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension. Eur Respir J
Frantz RP. Whither Anticoagulation in PAH? Conflicting Evidence REVEA Led. Circulation
Cirulis MM, Ryan JJ. Where do we go from here? Reappraising the data on anticoagulation in pulmonary arterial hypertension. J Thorac Dis
Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation
Farber HW, Miller DP, Poms AD, et al. Five-Year outcomes of patients enrolled in the REVEAL Registry. Chest
Herve P, Humbert M, Sitbon O, et al. Pathobiology of pulmonary hypertension. The role of platelets and thrombosis. Clin Chest Med
All authors contributed to the design and writing of this manuscript and approved the final version of this manuscript for publication.
Conflicts of interest
Checked twice by iThenticate.
Externally peer reviewed.