Use of Anticoagulants as a Supportive Measure in Pulmonary Hypertension: A Narrative Review

Abstract

Background

Pulmonary hypertension (PH) is a heterogeneous disorder with substantial morbidity and mortality. Thrombotic remodeling of pulmonary vasculature is a recognized contributor to disease progression, particularly in pulmonary arterial hypertension (PAH), prompting interest in anticoagulation as a potential adjunctive therapy. Despite the frequent use, anticoagulants continue to remain a controversial therapy across various subtypes of PH.

Methods

This review structurally evaluated published studies and evidence around the risks and benefits of anticoagulation across all five PH groups. Relevant peer-reviewed clinical trials, observational studies, and meta-analyses were identified through searches of PubMed, the Cochrane Library, and Google Scholar and were reviewed for survival outcomes, thromboembolic events, hemodynamics, and bleeding complications associated with anticoagulant use in PH.

Results

Evidence suggests that anticoagulation may provide a survival benefit in idiopathic PAH, while outcomes in connective tissue disease-associated PAH appear neutral or unfavorable due to increased bleeding risk. In other PH groups, anticoagulation has not demonstrated clear benefit and is generally reserved for standard indications such as atrial fibrillation or venous thromboembolism, except in chronic thromboembolic PH, where it remains a cornerstone of therapy.

Conclusion

There is currently no clear consensus on anticoagulation strategies across most PH subtypes (except group 4). Given the heterogeneity of PH, further well-designed prospective trials and PH-specific risk stratification tools are needed to clarify the role of anticoagulation and advance precision-based care in PH.

Key Figure

Introduction

Pulmonary hypertension (PH) is a complex and progressive disease with high morbidity and mortality [1]. Anticoagulants have been widely used as adjunctive therapy in addition to the main treatment, particularly in idiopathic and heritable forms of pulmonary arterial hypertension (PAH), based on proposed thrombotic and procoagulant mechanisms [2,3]. However, available evidence regarding their efficacy and safety remains inconsistent [4]. As a result, anticoagulation in PH is often guided by individualized risk-benefit assessment, balancing potential thromboembolic protection against bleeding risk [5]. This review critically examines the existing literature around the pathophysiologic rationale and clinical evidence supporting anticoagulant use across different PH subtypes.

Materials and Methods

This review examined the published literature evaluating the use of anticoagulants in PH across all five World Health Organization groups [6]. Eligible studies included peer-reviewed clinical trials, observational studies, and meta-analyses that assessed anticoagulation in relation to clinically relevant outcomes, including hemodynamics, survival, thromboembolic events, and bleeding risk. Commentary articles, expert opinions, and non– peer-reviewed sources were excluded.

A literature search was conducted using PubMed, the Cochrane Library, and Google Scholar with keywords related to PH and anticoagulation. Searches were limited to human studies published in English, and reference lists of included articles were screened for additional relevant publications. Full-text review focused on study design, patient population, type of anticoagulant used, outcomes, and adverse events. Findings were synthesized narratively to reflect current evidence across PH subgroups.

Results

1. Overview of pulmonary hypertension classification

PH encompasses a diverse group of conditions characterized by elevated pulmonary arterial pressure. According to the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines, PH is defined by a mean pulmonary arterial pressure (mPAP) >20 mm Hg with pulmonary vascular resistance (PVR) >2 Wood units [7]. PH is further classified into five subgroups based on etiology and pathophysiology [8] (Table 1).

Table 1.

Classification of pulmonary hypertension

PH group	Classification	Key features	Common causes and associated conditions	Management
Group 1	Pulmonary arterial hypertension (PAH)	Pre-capillary PH with elevated PVR and normal PAWP	Idiopathic, heritable, drug-induced, connective tissue diseases (e.g., SLE, scleroderma), HIV, CHD, portal hypertension	Targeted therapy (e.g., prostacyclin analogs, ERAs, PDE5 inhibitors), CCBs in responders, lung transplant in advanced cases [11]
Group 2	PH-LHD	Post-capillary PH due to elevated left atrial pressure	Heart failure with reduced/preserved EF, valvular disease	Treat underlying cardiac disease (e.g., diuretics, ACE inhibitors, beta-blockers) [14]
Group 3	PH due to lung diseases and/or hypoxia	Hypoxia-induced vasoconstriction and remodeling	COPD, ILD, OSA, high-altitude exposure, alveolar hypoventilation	Manage underlying lung disease, supplemental oxygen [17]
Group 4	PH due to pulmonary artery obstruction	Chronic thromboembolic obstruction	Chronic thromboembolic pulmonary hypertension (CTEPH)	Pulmonary endarterectomy, balloon pulmonary angioplasty, riociguat [18]
Group 5	PH with unclear/multifactorial mechanisms	Mixed or unclear pathophysiology	Hematologic disorders, chronic kidney disease, metabolic disorders, sarcoidosis	Treat underlying conditions; supportive care [8]

The table uses several abbreviations related to PH, its subtypes, associated conditions, hemodynamic parameters, and treatment classes: PH, PAH, and PH due to left heart disease (PH-LHD), as well as clinical measurements like PVR, PAWP, and EF. Additional abbreviations refer to associated diseases—including SLE, HIV, CHD, COPD, ILD, OSA, and CTEPH—and common therapeutic classes such as ERAs, PDE5 inhibitors, CCBs, and ACE inhibitors.

PH: pulmonary hypertension; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance; PAWP: pulmonary artery wedge pressure; SLE: systemic lupus erythematosus; HIV: human immunodeficiency virus; CHD: congenital heart disease; ERA: endothelin receptor antagonist; PDE5: phosphodiesterase-5; CCB: calcium channel blocker; PH-LHD: pulmonary hypertension due to left heart disease; EF: ejection fraction; ACE: angiotensin-converting enzyme; COPD: chronic obstructive pulmonary disease; ILD: interstitial lung disease; OSA: obstructive sleep apnea; CTEPH: chronic thromboembolic pulmonary hypertension.

Group 1 PAH is characterized by progressive remodeling and stiffening of the small pulmonary arteries, leading to elevated pulmonary vascular and pressure [9]. PAH includes hereditary, idiopathic, drug- and toxin-induced subtypes, as well as others associated with connective tissue diseases, human immunodeficiency virus (HIV) infection, portal hypertension, and congenital heart disease [10]. Some therapeutic management options for PAH include prostacyclin pathway agonists, endothelin receptor antagonists, nitric oxide-cyclic guanosine monophosphate enhancers, and sometimes calcium channel blockers. Pulmonary transplantation can be considered in treatment-refractory cases [11].

Group 2 PH results from left heart disease, leading to elevated left atrial pressure and pulmonary venous congestion, and is classified into isolated post-capillary PH and combined post- and pre-capillary PH, which differ by the PVR index [12,13]. Management targets treatment of the underlying left heart condition [14].

Group 3 PH is due to lung disease and/or hypoxia, such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), obstructive sleep apnea (OSA), to name a few, in which cases hypoxia-driven vasoconstriction leads to increased PVR [15,16]. The management again focuses on treating the underlying lung disease [17].

Group 4 PH is caused by chronic thromboembolic pulmonary hypertension (CTEPH) that leads to obstructions in the pulmonary arteries [6]. Management options include anticoagulation, with and without pulmonary endarterectomy, balloon pulmonary angioplasty (BPA), and a soluble guanylate cyclase stimulator–riociguat [18].

Lastly, group 5 PH includes conditions with multifactorial or unclear mechanisms, such as hematologic disorders, systemic and metabolic disorders, complex congenital heart disease, chronic renal failure, and disorders leading to pulmonary vascular occlusion or compression [6]. Management is focused on the identification and treatment of specific underlying conditions [8].

2. Group 1 PH: pulmonary arterial hypertension

1) Mechanisms of thrombosis in PAH.

Thrombosis is an important factor in the progression of PAH, contributing to elevated PVR and right-sided heart failure. This involves a multifactorial process with endothelial injury, dysregulated coagulation pathways, and structural changes within the pulmonary vasculature [19] (Figure 1).

Figure 1.

The pathophysiology of thrombosis in pulmonary arterial hypertension. Created in BioRender. Aghabekyan, T. (2026) https://BioRender.com/5l9bx2k. PDGF: platelet-derived growth factor; TGF-β: transforming growth factor-beta; RV: right ventricle.

PAH is associated with endothelial injury or dysfunction, which leads to an altered balance of mediators that regulate coagulation, vascular tone, and cell proliferation. For instance, endothelial dysfunction can lead to reduced levels of vasodilators like nitric oxide and prostacyclin, and increased levels of vasoconstrictors like endothelin-1 [20]. Additionally, a prothrombotic state is induced by the disequilibrium of the thrombotic and fibrinolytic balance, secondary to the chronic activation of the coagulation pathways [21]. Additionally, one study suggests that the levels of natural anticoagulants, such as thrombomodulin, may be decreased in PAH, further contributing to the prothrombotic state [22]. Importantly, the pulmonary artery wall thickening and gradual narrowing of the vessel lumen is at least partly driven by persistent inflammation and disrupted coagulation processes within the vasculature.

As the condition progresses, thrombi can become reorganized and further embedded in the vessel walls, ultimately limiting blood flow and increasing PVR [23].

2) Early observational data and trials supporting anticoagulation

Considering the high propensity for thrombi formation, the use of anticoagulants as a supportive measure in patients with PH has been an ongoing interest of researchers in the field of PH. Until the first comprehensive study in 2014, data were largely obtained from retrospective studies done in the 1980s–2000s, which suggested a positive survival benefit with anticoagulation therapy in patients with PH. For example, a study by Fuster et al. showed improved survival in patients receiving warfarin, while a different retrospective study from 1993 published results that supported the use of warfarin in combination with vasodilators (isoproterenol or nifedipine) for improved survival rate in patients with primary PH [4,24]. Multiple further studies also suggested that the anticoagulation therapy with warfarin might serve as an effective intervention in treating patients with PAH. However, the first larger-scale comparative prospective study was conducted in 2014 (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension [COMPERA] study). The study included 1,283 patients with newly diagnosed PAH, and the investigators studied the 3-year absolute survival in patients taking anticoagulation compared to those not taking it. The results of the study suggested that the use of anticoagulation therapy (whether vitamin K antagonists [VKAs], heparins, or direct oral anticoagulants [DOACs]) improved the 3-year survival in patients with idiopathic PAH (IPAH; hazard ratio, 0.79; 95% confidence interval, 0.66 to 0.94) [25].

3) Contrasting evidence and guideline recommendations for anticoagulants in group 1 PH

The use of anticoagulation therapy in management of PAH in the guidelines and expert opinions remains controversial due to the presence of conflicting evidence from never published research [7]. For instance, in 2015 Preston et al. [4] conducted an observational study to assess the effect of warfarin on survival in IPAH and systemic sclerosis-associated PAH (SSc-PAH) patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. Their methods included patients who initiated warfarin and those who had never taken warfarin. The survival analysis was performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias and the mean warfarin treatment was 1 year. The results showed no significant difference in survival with warfarin in IPAH patients or in SSc-PAH patients. Furthermore, SSc-PAH patients who received warfarin within the previous year or any time postbaseline had increased mortality in comparison with warfarin-naïve patients [24].

Another controversial finding was published in 2024 by Chen et al. [26] where they conducted a meta-analysis of 15 cohort studies to evaluate the effect of anticoagulation on the long-term survival of PAH patients. The results showed that there was no reduction in mortality rate or long-term survival rate, in patients with IPAH or connective disease-associated PAH receiving anticoagulant therapy [26].

Anticoagulants are commonly used as adjunctive therapy in patients with PAH; however, guideline recommendations differ across regions and centers due to the absence of large prospective randomized controlled trials (RCTs) [4]. One of the biggest concerns of anticoagulation therapy is the increased risk of bleeding events. Multiple studies were conducted to determine the bleeding risk in PAH patients that accept anticoagulation therapy as supportive care to prevent thrombosis. For instance, a study suggested that specific subgroups of patients with PAH (such as PAH linked to connective tissue disorder, congenital heart disease, and portopulmonary hypertension) receiving VKA had a higher risk of bleeding [27]. Another observational, retrospective cohort study compared the safety of routine administration of oral anticoagulants between PAH patients who were either receiving (intervention group) or not receiving (control group) oral anticoagulation from two medical centers. Understandably, the results showed that the intervention group had a higher bleeding incidence rate compared to the control group, thus suggesting that harm may outweigh benefits of anticoagulation in patients with PAH and further consolidating the need for case-by-case decision making [28].

Despite evidence from multiple observational, retrospective, and prospective studies, the role of anticoagulant therapy as supportive care in PAH remains controversial. Anticoagulation continues to be used in clinical practice, although the supporting evidence is limited, and international guidelines assign a class IIb-C recommendation, reflecting uncertain efficacy and reliance on expert opinion [7].

4) Warfarin vs. DOACs in PAH

Warfarin is a VKA, more commonly prescribed as anticoagulation in patients with valvular cardiac disease. However, with the recent advent of DOACs which are associated with superior safety profile and lower frequency of monitoring coagulation parameters, the question has transitioned to which class of anticoagulation has better outcomes in patients with PAH [29]. Data from observational studies including patients with IPAH and SSc-PAH have shown that DOACs may preserve antithrombotic efficacy of warfarin while at the same time reducing risks of major bleeding [25]. Rather than inhibiting the vitamin K-dependent clotting factors indirectly (as in the case of warfarin), DOACs directly target factor Xa or thrombin for more predictable anticoagulation with fewer interactions and monitoring needs [30]. The available evidence, however, remains largely nonrandomized, so definitive conclusions about superiority of DOACs over warfarin in PAH should be made cautiously.

3. Group 2 PH: PH due to left heart disease

1) Mechanisms

PH secondary to left heart disease, known as group 2, is a more prevalent form of PH [31]. Pathology is driven by underlying left heart disease, leading to retrograde pressure into pulmonary vasculature and passive pulmonary venous hypertension through congestion and eventual reorganization and fibrosis of the pulmonary vasculature [32]. These changes lead to endothelial injury and inflammation, and a procoagulant milieu that promotes microvascular clot formation in the pulmonary vasculature, further worsening the PVR and right heart strain [33].

2) Limited evidence supporting systemic anticoagulation in isolated PH-LHD

Anticoagulation therapy has not been specifically studied or established in patients with PH caused by left heart disease [34]. Unlike in CTEPH or atrial fibrillation (AF), where the role of anticoagulation is well defined, there is no clinical trial evidence supporting the routine use of anticoagulants in group 2 patients who do not have another clear indication [7]. AF and PH often occur concomitantly, especially in older adults [35]. When these two conditions coexist, the use of anticoagulation therapy becomes essential—not for primary management of PH, but rather to reduce the incidence of thromboembolic events associated with atrial fibrillation [36]. Nonetheless, group 2 PH itself may indirectly increase thrombotic risk by contributing to right atrial enlargement, stasis, and endothelial dysfunction, creating favorable factors for clot formation. Patients with heart failure who develop group 2 PH are often at increased risk of bleeding due to risk of renal and hepatic dysfunction that can occur in heart failure and impair drug metabolism and clearance as well as coagulation factor synthesis. Therefore, assessing the mechanism of action and sources of therapeutic clearance, whether renal or hepatic, is important for choice of anticoagulants [37].

4. Group 3 PH: PH due to lung disease/hypoxia

1) Mechanisms of thrombosis in COPD, ILD, OSA-associated PH

COPD, ILD, and OSA are all conditions proven to promote a prothrombotic state through hypoxia, inflammation, endothelial injury/dysfunction, and a subsequent altered hemodynamic parameter in the pulmonary vascular system [38]. In all the conditions mentioned above, chronic or intermittent hypoxia is a cardinal feature, which stimulates the expression of hypoxia-inducible factor-1α, increasing the production of tissue factor, plasminogen activator inhibitor-1, and von Willebrand factor. In turn, these procoagulant factors promote endothelial dysfunction, platelet activation and fibrin formation, and impair fibrinolysis [39]. Moreover, chronic lung diseases are often associated with low-grade systemic inflammation, which in turn enhances thrombogenicity by elevating levels of acute phase reactants like C-reactive protein, interleukin-6, and tumor necrosis factor-alpha [40].

Interestingly, in OSA, sympathetic surges caused by repetitive upper airway collapse contribute to increased platelet reactivity, oxidative stress, and high fibrinogen levels, further intensifying the risk of both systemic and pulmonary thrombosis [41].

2) Observational studies assessing anticoagulant use in chronic lung disease-related PH

Based on limited available observational evidence, anticoagulation is not routinely recommended in chronic lung disease-related pulmonary hypertension due to lack of clear benefits and potential risks [7]. In a Danish nationwide registry-based study assessing the risks of all-cause mortality associated with the use of various cardiovascular drugs in patients with COPD and right heart failure, oral anticoagulant use was associated with lower all-cause mortality compared with nonuse (hazard ratio of 0.87, 95% confidence interval, 0.79 to 0.95) [42]. Nonetheless, a treatment recommendation would require stronger evidence from prospective studies or randomized trials. Furthermore, patients with chronic lung diseases often also have heightened risk factors for bleeding—such as advanced age, comorbidities, steroid use, and frequent respiratory infections [43]. In this setting, there is still no clear benefit and added harm associated with anticoagulant use in group 3 PH. Therefore, clinical decisions should hinge on individual patient factors and comorbid conditions [7].

However, as discussed earlier, anticoagulation should still be reserved for clear alternative indications, such as AF or venous thromboembolism (VTE) [7]. Instead, therapy should focus on optimizing the underlying lung disease (e.g., supplemental oxygen, rehabilitation) and making individual decisions in specialized PH centers [44].

5. Group 4 PH: CTEPH

Anticoagulation therapy is a cornerstone of treatment for group 4 PH, also known as CTEPH [45]. This condition is caused by unresolved thromboembolic disease of the pulmonary vasculature, leading to persistent obstruction of pulmonary arteries and secondary vascular remodeling [46]. Since CTEPH originates from thromboembolic disease, all patients with confirmed CTEPH are recommended to receive lifelong anticoagulation, barring any contraindications, as recommended by the clinical guidelines of ESC and ERS [7]. The goal of anticoagulation is not only to prevent recurrent pulmonary embolism but also to minimize the risk of further thrombus propagation that could worsen PH [45]. This therapeutic approach distinguishes group 4 from other PH groups, where the role of anticoagulation is often less clear or not routinely advised [5].

A subset of patients with CTEPH can also be treated with specific interventions, such as pulmonary artery thromboendarterectomy or BPA [45]. However, despite the removal of obstructive thromboembolic material during surgery, patients with CTEPH remain at elevated risk for VTE due to underlying prothrombotic tendencies and chronic vascular changes [47]. The management of anticoagulation around the time of surgery in CTEPH requires a tailored approach that considers both thrombotic and bleeding risks [7].

Traditionally, VKAs such as warfarin have been the standard in the management of group 4, but DOACs are increasingly used in clinical practice despite limited data specific to CTEPH [48]. Emerging studies suggest that DOACs may offer a safe and effective alternative to warfarin for lifelong anticoagulation in CTEPH, though data remain limited and mostly observational. A large retrospective cohort study from Fuwai Hospital included over 300 patients and found similar survival and bleeding rates between DOAC and VKA users, but a higher rate of recurrent VTE (1.5% per person-year vs. 0.3% per person-year) in the DOAC group [49]. Furthermore, the KABUKI trial (Clinical Trial to Investigate Safety and Efficacy of Edoxaban in Patients With CTEPH), a multicenter, single-blind, randomized non-inferiority study, further explored this question by comparing edoxaban versus warfarin in CTEPH patients post-reperfusion therapy. After 48 weeks, edoxaban was found non-inferior to warfarin in preventing worsening PVR, with similar rates of clinically relevant bleeding and no reported thromboembolic events in either group [50]. Lastly, a multicenter systematic review and meta-analysis of prospective studies, including one randomized trial and cohort data totaling nearly 2,000 patients, revealed comparable mortality, VTE recurrence, and a trend toward reduced bleeding with DOACs [51].

In summary, while VKAs remain the guideline-recommended standard, emerging data suggest DOACs may offer a safe and effective alternative in carefully selected CTEPH patients. Their ease of use and potential for fewer bleeding events make them appealing, but their slight association with higher recurrent VTE underscores the need for cautious, individualized decision-making and further randomized studies to fully establish their role in PH treatment [49].

6. Group 5 PH: PH due to unclear/multifactorial mechanisms

1) Heterogeneous nature of group 5 PH

Group 5 PH is a broad and diverse category that includes conditions such as sarcoidosis, certain metabolic disorders (like Gaucher disease and glycogen storage diseases), blood-related diseases (including sickle cell disease and myeloproliferative syndromes), and other systemic illnesses [52]. Postulated causes include compression or structural changes in the pulmonary vessels, increased blood thickness, damage from chronic hemolysis, low oxygen levels, elevated cardiac output, or even dysfunction on the left side of the heart [53]. Since the etiologies and clinical manifestations vary so significantly, evaluation and management become challenging. Additionally, there is limited research and very few clinical trials focused specifically on this group, so treatment is typically centered on managing the primary condition driving the PH [54]. For example, reducing inflammation in sarcoidosis or improving blood-related complications in sickle cell disease may help ease PH symptoms [7]. In some cases, PH-specific therapies may be considered, but this is usually done on a case-by-case basis due to the lack of broad evidence [55].

The various disorders within group 5 PH have varying associated risks of thrombosis or bleeding, which is why consistent guidelines and recommendations will remain a challenge to achieve [54]. Moreover, most existing studies focus on specific diseases rather than group 5, and specifically randomized clinical trials are lacking [7].

2) Potential indications in hypercoagulable conditions

In general, in patients with group 5, anticoagulation may be considered when the underlying condition is associated with a hypercoagulable state [54]. Conditions include myeloproliferative disorders, sickle cell disease, and systemic lupus erythematosus with antiphospholipid syndrome (APS) [52]. In these cases, the decision to use anticoagulation is not driven by the PH itself, but rather by the coexisting risk for VTE or arterial thrombosis [56].

Myeloproliferative neoplasms (MPNs), especially polycythemia vera and essential thrombocythemia, are associated with increased thrombotic risk due to increased blood viscosity and platelet quantity. In these patients, low-dose aspirin or anticoagulation may be indicated depending on their thrombotic history and individual risk factors [57].

In sickle cell disease, chronic hemolysis can lead to a prothrombotic state, and anticoagulants may be considered in those patients with a prior history of VTE or suspected chronic thromboembolic disease [56]. APS is a known prothrombotic condition and often associated with underlying connective tissue diseases, typically requiring lifelong anticoagulation, especially if one has a history of a thrombotic event [58].

In conclusion, while there are limited potential indications, the lack of strong overall evidence in group 5 suggests that treatment must be individualized [25].

Discussion

1. Comparative summary of anticoagulation risks and benefits across PH subtypes

Overall in group 1 PH, observational data and meta- analyses have shown a possible survival benefit with anticoagulation, especially with VKAs such as warfarin. The COMPERA registry demonstrated improved 3-year survival in anticoagulated IPAH patients (hazard ratio approximately 0.79) [25]. However, in connective tissue disease-associated PAH like systemic sclerosis, the benefits are less clear, and bleeding risk may outweigh potential advantages. Registries such as Pulmonary Hypertension Association Registry have found higher rates of major bleeding and increased healthcare utilization without clear mortality benefit in these subgroups [59,60]. Reflecting this uncertainty, guidelines regarding anticoagulant use diverge: the ESC/ERS 2022 guidelines recommend anticoagulation for IPAH and certain subtypes (class IIa/B) but advise against routine use in connective tissue-associated PAH [7]. The American College of Cardiology/American Heart Association guidelines similarly suggest warfarin in select high-risk PAH scenarios (e.g., idiopathic, anorexigen-induced, or advanced cases) but emphasize individualized decision-making due to limited evidence in subgroups [60].

In group 2 PH, there is no evidence supporting anticoagulation solely for PH. Anticoagulation is only pursued for other standard indications—such as AF or VTE—but not for PH itself. Bleeding risk must be managed based on comorbidities and disease severity [61]. As a result, the 2022 ESC/ERS guidelines clearly discourage using PAH-specific anticoagulant therapy in PH-LHD, particularly in isolated post-capillary PH, due to concerns about safety and lack of proven benefit [7]. Instead, management focuses on optimizing treatment of heart failure, volume status, and comorbidities, with interventions like diuretics or angiotensin-converting enzyme inhibitors, not anticoagulants, unless justified by separate indications such as AF or VTE [62].

In group 3 PH, evidence from observational studies is sparse and mixed. Studies in chronic lung disease-associated PH like COPD have not demonstrated a mortality benefit from anticoagulation, and bleeding risk may be higher in frail or comorbid patients, particularly those on steroids [24]. As a result, guidelines do not recommend routine anticoagulation in group 3 unless there is an independent indication such as documented VTE or AF [7].

In contrast to other PH groups, group 4 or CTEPH has a clear, well-established indication for anticoagulation. All patients with confirmed CTEPH should receive lifelong anticoagulation—even after pulmonary endarterectomy or BPA—to prevent recurrent thromboembolism and disease progression [7]. The expert consensus is strong despite the absence of randomized trials, given high morbidity and mortality from recurrent thrombosis [48].

In group 5 PH, because of substantial heterogeneity, no randomized or robust evidence exists to support routine anticoagulation. Anticoagulation is considered on a case-by-case basis, particularly in patients with hypercoagulable disorders like MPNs or APS where thrombotic risk is high [7]. Clinical decisions must weigh individual bleeding and thrombotic risk profiles due to the variability in disease mechanisms [55].

Practical decision-making in specific clinical contexts, however, can be a big challenge for physicians. For example, in a 65-year-old man with IPAH (group 1), well-controlled on PAH therapy, no comorbidities—anticoagulation would be strongly considered given his favorable risk-benefit profile. On the other hand, in a 78-year-old woman with group 2 PH due to heart failure with reduced ejection fraction, and a history of gastritis—anticoagulation should be avoided due to high bleeding risk outweighing any potential benefit. These examples underscore the need for individualized assessment across PH groups.

2. Future research priorities

Even though there have been major improvements in how we understand and treat PH, there’s still a lack of strong, high-quality research, especially when it comes to how anticoagulation should be used across different types of PH. A lot of what we know so far comes from observational studies and patient registries such as COMPERA, which are helpful but have limitations. Because these studies look back at existing data rather than testing treatments in real time, they can’t fully answer important questions, such as which patients benefit most from anticoagulation or how treatment should differ depending on the cause of PH or patient’s comorbidities. For these reasons, there is a clear need for prospective, RCTs to better understand and guide anticoagulation use in various PH subgroups.

Moreover, there is a compelling need to develop PH-specific risk stratification models that combine thrombotic and bleeding risk profiles tailored to the subtype of PH and individual characteristics. Existing risk models such as the REVEAL 2.0 score and the ESC/ERS four-stratum framework offer validated tools for predicting outcomes in PAH and guiding therapy intensity. These models incorporate functional status, biomarkers like N-terminal pro-B-type natriuretic peptide, exercise tolerance, and hemodynamic data to project survival and treatment response in groups 1 and 4 PH [63]. However, they don’t directly inform anticoagulation decisions and cannot reliably capture the nuances of thrombotic risk versus bleeding potential at an individual level. Rather, the development of newer prediction models would help clinicians make informed decisions while balancing efficacy and safety and move away from global general recommendations on anticoagulation strategies toward precision-based approaches.

In conclusion, there is no clear consensus for anticoagulation strategy in different types of PH (with the exception of group 4 PH) and recommendations on supportive care differ among PH groups. Given the heterogeneity of PH, a uniform anticoagulation strategy is unlikely to be appropriate or conceivable. This underscores the need for future research on comparative effectiveness of different anticoagulant agents, and personalized medicine approaches that will optimize clinical benefit, reduce harm, and provide clearer guidance across PH subtypes.