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EDITORIAL
Year : 2023 | Volume
: 69
| Issue : 4 | Page : 187-189
Chronic thromboembolic pulmonary hypertension – Time is of the essence
V Taskar
Correspondence Address:
Dr. V Taskar
Professor of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wellstar – MCG Health
USA
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jpgm.jpgm_707_23
How to cite this article:Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed form of pulmonary hypertension (PH) that is the result of previously symptomatic or asymptomatic pulmonary embolism (PE).[1] Data obtained from multiple registries worldwide suggest that these patients constitute approximately 18% of the population seen in a PH center.[2] There is a 2.8% cumulative incidence of CTEPH, 8 years after a first unprovoked PE.[3] However, the true prevalence of CTEPH is higher and includes patients with no known prior pulmonary emboli. Indeed, the association between CTEPH and prior DVT and PE is not always present, as demonstrated by an international prospective registry, where this association was present in only 56% of patients.[4] Early recognition and treatment are of paramount importance because CTEPH progressively results in right heart failure, limiting life expectancy. The COVID-19 pandemic and the increased thromboembolic events following an overt or silent COVID-19 infection and vaccine-induced thrombosis highlighted the interaction of acute infection and its impact on thrombogenicity.[5],[6] Unfortunately, long-term follow-up of individuals labeled as post-COVID syndrome may occur with various disciplines not familiar with CTEPH in a resource-poor setting. The importance of a consistent, systematic approach in ruling out CTEPH in the workup of any new onset dyspnea, with accompanying findings of PH by echocardiography (ECHO) and ventilation perfusion (VQ) scanning is hereby reiterated. The objective of this editorial is to heighten the awareness of CTEPH, thereby hastening diagnosis and therapy.
After an acute symptomatic or asymptomatic episode of PE, 30%–50% of patients have unresolved clots for up to a year after the event. The incompletely resolved thrombi get organized into fibrotic material that obstructs the pulmonary artery causing PH. There is usually a honeymoon period during which the patient may be asymptomatic; however, ultimately, dyspnea, hypoxemia, and right ventricular dysfunction will ensue.[7] The ESC/ERS Guidelines in 2022 defined CTEPH (WHO Group 4) as precapillary PH with mean pulmonary artery pressure greater than 20 mmHg that persists after 3 months of anticoagulation with at least one segmental perfusion defect on VQ imaging and typical findings on computerized tomography (CT) and pulmonary angiography (PA).[8] Though every effort must be made to prevent thrombus formation, PE is prevalent in both provoked and unprovoked settings.
The mortality and morbidity from acute PE have led to the deployment of Rapid PE Response Teams (PERT), similar to acute myocardial infarction or acute stroke teams. The aim of PERT is to reduce the time between the patient presenting to the emergency room, the diagnosis of massive PE being made, and receiving intravenous or catheter-directed thrombolysis.[9] Since 2014, at least two meta-analyses and up to 15 randomized controlled studies favored the use of catheter-directed thrombolysis versus systemic thrombolysis vs no thrombolysis in high-risk and intermediate high-risk PE to reduce all-cause mortality.[10] These device-based therapies may be feasible in specialized centers but are not available in semi-rural and rural settings worldwide. Systemic anti-coagulation remains the staple therapy unless contraindicated due to excessive bleeding risks. Close follow-up of these patients would be ideal to facilitate early diagnosis of CTEPH. Klok et al.[11] published CTEPH prediction scores by using weighted measures such as unprovoked PE (+6), known hypothyroidism (+3), symptom onset >2 weeks before PE diagnosis (+3), right ventricular dysfunction on CT or ECHO (+2), known diabetes mellitus (−3), and thrombolytic therapy or embolectomy (−3).
Making an accurate diagnosis of CTEPH is of paramount importance as 99% of patients present with dyspnea, which is frequently attributed to age, deconditioning after an acute illness, cardiopulmonary disease, or obesity. In the setting of dyspnea, an echocardiogram (ECHO) and a VQ scan should be part of the diagnostic algorithm even in resource-poor settings.[12] CTEPH may occur in conjunction with other etiologies of PH such as human immunodeficiency virus, mixed or undifferentiated connective tissue disease, and sickle cell disease. Pulmonary conditions such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD) and systolic and diastolic heart failure may coexist with CTEPH. The last decade has seen revisions of the PH definition to promote earlier detection and appropriate therapy considering the prognostic relevance of increased pulmonary arterial pressure.[8]
Pulmonary endarterectomy (PEA), pulmonary vasodilator therapies, and balloon pulmonary angioplasty (BPA) are accepted modalities for treating CTEPH.[13] PEA is considered the first-line therapy; however, the proportion of inoperable CTEPH may vary from 10% to 50%. Reasons for inoperability may include surgically inaccessible disease, small vessel disease, comorbidities, and age. It is important to note that operability is subjective and dependent on the respective center's experience. A commonly cited cause of inoperability is distal pulmonary vascular obstruction; however, distal endarterectomies are possible in the hands of experienced surgeons. In expert centers, defined by >50 procedures per year, the mortality is lower than 5%, the improvement in pulmonary vascular resistance is immediate and the 3-year postoperative survival is up to 89% compared to 70% for those without PEA.[14] However, over 50% of operated patients eventually develop persistent PH, emphasizing the need to establish registries and institute long-term follow-up. A proportion of these patients may have segmental pulmonary arterial obstruction amenable to BPA, depending on the anatomy and the available surgical expertise.[15] BPA has been proposed as an adjunct to medical therapy as well, in patients with residual PH following PTE.[16]
The last three decades have seen an immense improvement in our understanding of the mechanistic pathways in precapillary pulmonary arterial hypertension, identification of newer therapeutic targets, and clinical studies demonstrating the effectiveness of combination therapies to the extent that parenteral therapy is reserved for only the most severe patients not responsive to oral agents.[17] This has simplified PH care; however, access to these medications remains a challenge due to the prohibitive costs, side effects, and need for titration and monitoring. PH care needs a dedicated team of nurses and clinical pharmacists who can work with the patients to ensure timely and appropriate management. Riociguat, a guanylate cyclase stimulator, is the only FDA-approved medical therapy for CTEPH. Using results from a 6-min walk distance (6MWD) test, the riociguat group had a mean improvement of 46 m (95% CI: 25–67 m, P < 0.0001) along with a significant improvement in pulmonary vascular resistance.[18] However, the use of riociguat should not be considered until the workup of operability is fully completed and contraindications to riociguat use are thoroughly eliminated (e.g., pregnancy and concomitant use of phosphodiesterase-5 (PDE5) inhibitors and nitrates/nitric oxide medications). Data comparing BPA versus riociguat in inoperable CTEPH show a greater decrease in PVR with BPA but no difference in 6MWD.[18] Furthermore, BPA is associated with more serious adverse events, such as hemoptysis and lung injury.[15],[19] Yang et al.[17] summarized the clinical studies utilizing bosentan (BENEFIT), macicentan (MERIT-1), subcutaneous treprostinil (CTREPH), and selexipag in CTEPH in conjunction with surgery.[17] Data on the use of combination therapy for CTEPH is emerging but is sparse.
There are a limited number of PH centers in India, and even fewer centers can perform PEA and BPA or have a dedicated PH specialist to coordinate PE/PH care. Maligireddy et al.[20] painstakingly explored the gaps in PH care in India. This article is recommended for anyone practicing in India to become aware of not only the disease, but also of potentially correctable gaps in PH care. No data from Mumbai or Maharashtra were included despite the profusion of advanced medical centers in the region, highlighting the need for an organized approach to PH care.
Interdisciplinary care – it takes a village.
PE is frequently managed by internists, hospitalists, pulmonologists, and cardiologists. Interventional radiologists and cardiologists who focus on reducing thrombus burden must get involved early in the course to determine if an intervention is indicated. It is important to develop a consensus within a hospital system in terms of recognizing thromboembolism, timely treatment with thrombolytics or non-surgical thrombectomy when indicated, and following up with these patients long-term for development of PH. Hematologists should be involved in managing individual risk factors for increased propensity for thrombus formation. Cardiothoracic surgeons have to develop experience in performing endarterectomies. Nurses and clinical pharmacists do help in obtaining medications, educating patients about medication side effects, titrating to optimize dosing, and are an integral part of the “PH Care Team.”[21]
In summary, CTEPH is a potentially treatable condition whose devastating outcomes can be mitigated by early diagnosis, thrombolytics, and non-surgical thrombectomy in the acute phase and referral for endarterectomy in the chronic stage. Medications used in idiopathic pulmonary arterial hypertension have shown benefit in multiple studies; however, obtaining and monitoring for side effects is costly and time-consuming. These patients remain on anticoagulation life-long and treating any additional risk factors that promote the hypercoagulable state should not be neglected.
Acknowledgement
The author is grateful to Amit Krishnan BS, MD candidate at the New York Medical College for his involvement in adding content, formatting the manuscript, and organizing references.
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