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Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy

Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy
Literature review current through: Jan 2024.
This topic last updated: Aug 16, 2023.

INTRODUCTION — The natural history of chronic thromboembolic pulmonary hypertension (CTEPH) is typically one of progression to right heart failure and death. Pulmonary artery thromboendarterectomy (PTE), variably referred to as pulmonary endarterectomy (PEA) is the only definitive and potentially curative therapy for CTEPH. However, PTE is a major thoracic surgery and selecting ideal candidates is critical for its success. Medical therapy is noncurative and is generally reserved for those who are not operative candidates or patients who fail or decline PTE.

The approach to initial management, evaluation, and selection of patients with CTEPH for surgical or medical therapy are reviewed here. Guidelines set forth by the 6th world symposium on pulmonary hypertension (PH) are in general followed in this topic [1]. The clinical presentation, diagnostic evaluation, and administration and outcomes of surgical and medical therapy are described separately. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension" and "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy" and "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy".)

The approach outlined in this topic is, for the most part, consistent with guidelines set out by several international societies [1-4].

ANTICOAGULANT THERAPY (INDEFINITE) — The first step in the management of CTEPH is the immediate initiation of anticoagulant therapy, provided the patient is not at a high risk of bleeding. In those who are at high risk of bleeding, we typically place an inferior vena cava filter until the bleeding risk is resolved and adequate anticoagulation can be provided. Our approach is based upon the biologic rationale that anticoagulant therapy prevents further thromboembolism and indirect data from patients who undergo anticoagulation for acute thromboembolism [5]. In our experience recurrent thromboembolism is rare and most often due to subtherapeutic anticoagulation.

Agent – Once a diagnosis of CTEPH is in place, we immediately treat patients with anticoagulant therapy using intravenous unfractionated heparin, subcutaneous low molecular weight (LMW) heparin, or a direct oral anticoagulant (DOAC; eg, rivaroxaban or apixaban can be used without a short course of LMW heparin).

For long-term management, we typically choose either a vitamin K antagonist (VKA; warfarin) or a DOAC. Historically, warfarin was the agent of choice, although DOACs are now often used based upon their efficacy in patients with acute venous thromboembolism (VTE) (see "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors'). Data regarding the efficacy of DOACs in patients with CTEPH are limited and conflicting. While retrospective data demonstrated a possible higher rate of thromboembolic recurrence associated with use of DOACs compared with warfarin [6,7], other retrospective data demonstrated that rivaroxaban was a safe alternative to warfarin without an increase in recurrent venous thromboembolism [8]. Bleeding rates appear to be similar with both agents [7,8].

For patients treated with warfarin, the target International Normalized Ratio (INR) is 2 to 3. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Warfarin'.)

For patients in whom DOACs are chosen, the risk of drug-drug interaction mediated by P-glycoprotein and cytochrome 3A4 should be taken into consideration. Among the available DOACs, no one agent is preferred. Agent choice and dosing are provided separately. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors'.)

Factors that influence the choice of anticoagulant (table 1) are discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation", section on 'Selection of agent'.)

Duration – Therapeutic anticoagulation is continued indefinitely, regardless of whether patients are treated surgically or medically. Interruption and resumption of anticoagulation for procedures or surgery is discussed separately. (See "Perioperative management of patients receiving anticoagulants".)

Efficacy – Despite the widespread practice, there are no studies in patients with CTEPH comparing indefinite anticoagulant therapy with either no therapy or a shorter duration of therapy. The rationale for anticoagulant therapy is based upon the following:

Our clinical experience and the assumption that the thromboembolic event resulting in CTEPH represents a "pro-thrombotic" state. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Pathogenesis'.)

Data from patients with acute pulmonary embolus, which demonstrate an increased risk of recurrence once anticoagulation is discontinued, and a reduction in recurrent VTE with prolonged anticoagulation compared with anticoagulation of a shorter duration or no therapy. These data are discussed separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Warfarin' and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Direct oral anticoagulants (factor Xa and direct thrombin inhibitors)'.)

CTEPH CENTER REFERRAL — Optimal timing and material needed for referring patients with suspected CTEPH include the following:

When to refer – For patients with suspected CTEPH, we advocate early referral to a CTEPH center (ie, as soon as the diagnosis is suspected and reasonably supported with data). The referral should not be delayed even if the symptoms, hemodynamic abnormalities, or ventilatory impairment seem mild. The purpose of the evaluation is to reconfirm the diagnosis of CTEPH, obtain further testing, if necessary, and develop an appropriate therapeutic approach whether it be PH-specific medical therapy, balloon angioplasty, or pulmonary thromboendarterectomy (PTE). If PTE is delayed, the development and progression of a secondary vasculopathy may result in a sub-optimal hemodynamic outcome from PTE and may increase the mortality risk associated with the procedure.

CTEPH referral center – At minimum, the center should have experience in evaluating and treating patients with CTEPH. The evaluation in specialist centers is undertaken by a multidisciplinary team that typically consists of a surgeon with experience in performing PTE (ideally >50 cases/year with a mortality rate of <5 percent), PH experts with experience in the treatment of PH, radiologists with experience in imaging CTEPH (eg, digital extraction pulmonary angiography), and intensivists who are adept at managing these patients in the critical postoperative period. CTEPH centers are now also gaining expertise in percutaneous pulmonary artery balloon angioplasty (BPA), mostly performed by interventional cardiologists, although experience in BPA is not yet a prerequisite for defining CTEPH center expertise.

Data needed for referral – Useful data for a referring PH center to include are the following:

Documentation of a comprehensive clinical history and examination supporting PH and CTEPH

Patient’s functional class (table 2) and six-minute walk test

Relevant comorbidities

Pulmonary function tests

Transthoracic echocardiography report

Results from investigative laboratory reports (eg, HIV status, liver function tests)

Radiology imaging documenting anatomic assessment from at least two imaging modalities (eg, ventilation/perfusion scanning, computed tomography [CT] of the chest or CT pulmonary angiography, magnetic resonance pulmonary angiography or invasive pulmonary angiography)

Pulmonary artery catheter (PAC) results (if available)

These data are typically performed as part of the diagnostic investigation for PH and for CTEPH. While most PH centers perform PAC and in some cases pulmonary angiography, prior to referral, both tests can be readily performed simultaneously at the CTEPH center and as such, are not absolutely necessary for referral. Details regarding the investigation of suspected PH and CTEPH are provided separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

EVALUATION FOR PULMONARY THROMBOENDARTERECTOMY

General principles — Because pulmonary thromboendarterectomy (PTE) is the only potentially curative therapy for patients with CTEPH, we evaluate all patients for PTE (algorithm 1). We evaluate patients even if the symptoms, hemodynamic abnormalities, or ventilatory impairment seem mild because early surgery may prevent the development of a secondary, small-vessel vasculopathy, which may make the patient less likely to be suitable for surgery or may contribute to post-PTE residual PH [9].

The decision to proceed to PTE in a patient with CTEPH involves complex decision-making, which involves an interplay among the answers to the following questions:

Is there significant hemodynamic or exercise impairment?

Are the chronic thromboemboli accessible to surgery?

What is the anticipated postoperative hemodynamic outcome?

Are there comorbid conditions affecting surgical candidacy?

Are there patient preferences that impact the decision?

The main focus of the evaluation is to determine whether removal of thromboembolic material would sufficiently reduce the pulmonary artery vascular resistance (PVR). The latter assessment is critical since outcomes are dependent upon the effect of PTE on PVR. Outcomes are favorable when PVR decreases. In contrast, failure of the PVR to decrease following PTE is associated with poor short-term outcomes (inability to wean from cardiopulmonary bypass, early postoperative hemodynamic instability, early postoperative death) and poor long-term outcomes (eg, residual PH) [9-11]. This is particularly true among patients with severe PH and right ventricular dysfunction. Since routine objective parameters are lacking [12], this assessment should only be undertaken at specialized CTEPH centers by clinicians familiar with the disease process and its management, thereby ensuring optimal patient selection.

In a European registry, approximately one-third of patients with CTEPH were deemed inoperable based upon several factors including the distal nature of their pulmonary artery obstruction, an imbalance between the severity of PH and the radiographically visible morphologic lesion, a PVR greater than 1500 dynes-sec/cm-5 (>19 Wood units), older age, or the presence of a comorbidity prohibiting surgery [13]. With improvements in imaging technology, surgical techniques, and postoperative management, the number of patients deemed inoperable at expert centers has fallen.

Is there significant hemodynamic or exercise impairment? — In order to assess the hemodynamic impairment from CTEPH, we re-examine pulmonary artery catheterization (PAC) data (algorithm 1).

Patients with substantial hemodynamic abnormalities at rest – Patients in this category are most likely to benefit from PTE. Most patients undergoing evaluation for PTE have hemodynamic abnormalities at rest that almost invariably warrant surgery (eg, PVR of 160 to 1200 dynes-sec/cm-5 [2 to 15 Wood units] with the majority falling into the range of 600 to 1000 dynes-sec/cm-5 [7.5 to 12.5 Wood units]).

Although the perioperative mortality risk increases with the level of the preoperative PVR, we still consider PTE in those with very high PVR, as long as the anticipated reduction in PVR based on the hemodynamic and angiographic findings obtained in the evaluation process will result in a postoperative PVR ≤500 dynes-sec/cm-5 (6.25 Wood units).

This estimate of PVR reduction is a subjective one involving an evaluation of the degree of PH, the extent of surgically accessible thrombus, and the contribution of a secondary vasculopathy to the elevated PVR and is best obtained by those with considerable expertise in the disease process.

Patients without substantial hemodynamic impairment at rest – In patients without substantial hemodynamic impairment at rest, we test the pulmonary hemodynamic response to exercise during PAC (eg, PVR <160 dynes-sec/cm-5 [<2 Wood units]) using either cycle ergometry or the repetitive lifting of hand weights intended to increase the cardiac output (varies among centers).

For patients in whom exercise-induced PH is found, we still consider PTE as potentially beneficial. An increase in pulmonary artery pressures with exercise suggests that the patient's right ventricular workload increases during their activities of daily living, thereby resulting in exercise limitation, which may result in long-term progression of their PH, thereby justifying PTE.

For patients without a substantial increase in pulmonary hemodynamics with exercise, the benefits of PTE are less clear. In such cases we consider PTE when the patient’s exercise intolerance and quality of life dissatisfaction is of sufficient magnitude that the patient is willing to accept the risk of surgery.

Are the chronic thromboemboli accessible for surgery? — For patients with CTEPH, we use imaging to determine whether chronic thromboemboli are accessible for surgery. Only thromboembolic disease located proximally in the main, lobar, or segmental pulmonary arteries are amenable to surgical removal while distal disease is not typically surgically accessible (algorithm 1).

Digital subtraction pulmonary angiography (DSPA) is considered the gold standard in defining the extent and location of the thromboembolic obstruction. However, with improving expertise at experienced centers, an increasing number of patients with distal disease (ie, segmental or subsegmental thromboemboli) may undergo surgery with acceptable hemodynamic and functional outcomes [14,15].

In patients with profound right ventricular failure and shock, the risk of DSPA may be prohibitive to this assessment. In such patients, we use less invasive imaging studies such as computed tomographic pulmonary angiography (CTPA) or magnetic resonance pulmonary angiography (MRPA).

In patients with suspected CTEPH who have a known contrast allergy or renal insufficiency, every attempt should be made to perform contrast-enhanced studies. If absolutely contraindicated, then CTPA and MRPA can be used. (See "Allergy evaluation of immediate hypersensitivity reactions to radiocontrast media" and "Diagnosis and treatment of an acute reaction to a radiologic contrast agent" and "Radiocontrast hypersensitivity: Nonimmediate (delayed) reactions" and "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast-associated acute kidney injury related to angiography".)

What is the anticipated postoperative hemodynamic outcome? — For patients with CTEPH, we perform a gestalt estimate of what the anticipated hemodynamic outcome will be following PTE. This is the most crucial aspect of the preoperative evaluative process. We determine whether the degree of PH measured on PAC is consistent with the extent of accessible thromboembolic material seen on imaging (DSPA and/or CTPA) and estimate the hemodynamic improvement that might be achieved with PTE. This assessment is subjective requiring an experienced, multidisciplinary team including chest radiologists, cardiothoracic surgeons, and pulmonary vascular experts who are familiar with CTEPH and its management.

If it is assessed that most of the chronic thromboemboli are proximal (ie, surgically accessible) and the majority of the elevated PVR is due to proximal disease, then PTE is more likely to be successful and result in normalization or near-normalization of PVR.

In contrast, if most of the chronic thromboemboli are distal or the majority of the elevated PVR is due to a distal vasculopathy, PTE may not sufficiently lower the PVR resulting in a suboptimal response, postoperative right ventricular (RV) failure, hemodynamic instability, or death.

In many patients, especially those with longstanding disease, the elevated PVR is related to both accessible thromboembolic disease, which is surgically remediable, and to the presence of a distal vasculopathy which is not. Considerable experience with the disease process and angiographic interpretation is required to determine the contribution of each and to estimate the hemodynamic improvement that can be achieved with surgery.

Are there comorbid conditions affecting surgical candidacy? — PTE is best performed in those at low risk for major thoracic surgery. We assess the risk in a similar fashion to those undergoing other forms of thoracic surgery (algorithm 1). (See "Evaluation of perioperative pulmonary risk" and "Strategies to reduce postoperative pulmonary complications in adults" and "Evaluation of cardiac risk prior to noncardiac surgery".)

The presence of comorbid conditions, with the exception of those that are end-stage, do not typically represent an absolute contraindication to PTE. Age is not a contraindication to surgery and patients up to 80 years of age have successfully undergone a PTE.

Risk factors for a less favorable outcome after PTE surgery, although not absolute contraindications, include the following:

An absent history of deep venous thrombosis (DVT) or pulmonary embolus (PE)

World Health Organization (WHO) functional class IV (table 2)

Significant concomitant lung or left heart disease

Right heart failure

PVR greater than 1200 dynes-sec/cm-5 (15 Wood units)

Inconsistencies between different imaging modalities [1]

Absence of appreciable lower lobe disease

Significant underlying pulmonary or left heart disease

We carefully review with the patient any increased risks imposed by coexisting conditions on both perioperative and long-term hemodynamic and functional outcomes before the decision is made to proceed to surgery.

Are there patient preferences that impact the decision? — As for all surgical procedures, we have a detailed discussion with the patient regarding the potential benefits (ie, the extent of hemodynamic and functional improvement), and the risks of morbidity and mortality associated with PTE. Patient and family cooperation are very important during the postoperative period and it is important that the patient and their family are motivated and engaged.

OPERABLE CANDIDATES

Pulmonary artery thromboendarterectomy — For patients with CTEPH who are operable candidates, we suggest pulmonary artery thromboendarterectomy (PTE) rather than PH-specific therapy (algorithm 1). Following PTE, anticoagulation is routinely continued.

This approach is based upon the rationale that PTE is the only potentially curative option and data in suitable candidates that support low perioperative mortality (<3 percent in those with a pulmonary artery vascular resistance [PVR] <800 dynes-sec/cm-5 [10 Wood units]) as well as improved pulmonary hemodynamics, functional status, and long-term survival. Although PTE has not been directly compared with PH-specific therapy, outcomes with medical therapy are comparatively modest. The technique and outcomes from PTE and PH-specific therapy are discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy" and "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy".)

We prefer early intervention within days to weeks following the diagnosis of CTEPH to avoid the development or progression of a secondary, distal vasculopathy, which is not amenable to surgical correction. However, patients in whom PTE needs to be deferred (eg, PTE declined by the patient or medical condition needs to be optimized) are closely followed using clinical assessment of their functional status (table 2) and hemodynamic status (eg, repeat echocardiography and/or pulmonary artery catheterization) so that PTE can be reconsidered at a later date.

Medical therapy as a bridge to surgery (not routine) — We suggest not routinely administering PH-specific therapy as a bridge to surgery, although reports suggest that it is being increasingly utilized [5,9,16]. Although preoperative PH-specific medical therapy can result in improvements in both hemodynamic and functional status, there is no evidence to suggest that it lowers the mortality risk associated with PTE, and it may result in a significant delay in time to referral for the procedure [16,17].

The only exceptions are patients with right ventricular failure and/or severe PH [9]. In such cases, PH-specific medications and/or extracorporeal membrane oxygenation (ECMO), typically venoarterial ECMO may be used as a life-saving measure to hemodynamically stabilize the patient, giving sufficient time to proceed with surgery more safely. If the decision is made to temporarily proceed with medical therapy, the patient should be managed as described separately. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy" and "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy", section on 'Bridge to surgery' and "Extracorporeal life support in adults: Management of venoarterial extracorporeal membrane oxygenation (V-A ECMO)", section on 'Acute decompensated pulmonary vascular disease'.)

INOPERABLE CANDIDATES — For most patients with CTEPH who are not suitable for pulmonary artery thromboendarterectomy (PTE), we suggest treatment with PH-specific therapy (algorithm 1). (See 'Pulmonary hypertension-specific therapy' below.)

For those who fail PH-specific therapy, options include percutaneous balloon pulmonary angioplasty (BPA), or a multimodal approach using a combination of PH-specific therapy and BPA, although data to support these options are less robust. (See 'Percutaneous balloon pulmonary angioplasty' below and 'Combined therapy' below.)

For patients with refractory CTEPH who are not candidates for or have failed all options (PTE, PH-specific therapy, and BPA), evaluation for lung transplantation may be the only option. (See 'Double lung transplantation' below.)

Pulmonary hypertension-specific therapy — For patients who are not PTE candidates or patients who decline or delay PTE, we suggest PH-specific therapy in addition to anticoagulation rather than anticoagulation alone. While medical therapy is not curative, it is the main option for this group with data that support only modest improvements in exercise tolerance and pulmonary hemodynamics when compared with PTE. These data are discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy".)

We also use PH-specific therapy for patients with residual PH following surgery and in rare circumstances, in patients with severe PH who need a bridge to surgery. These data are discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy" and 'Medical therapy as a bridge to surgery (not routine)' above.)

Other options

Percutaneous balloon pulmonary angioplasty — While in the past, percutaneous BPA was associated with high rates of morbidity and mortality, it has become an effective therapeutic intervention with newer, more refined techniques, and increasing experience at CTEPH centers. However, patient selection has not been fully defined and outcomes have not been compared with PTE or PH-specific therapy (algorithm 1).

Limited observational data suggest a potential role for percutaneous BPA in select patients with inoperable CTEPH, in patients with residual PH following PTE, or in patients who fail or have marginal benefit from PH-specific therapy. BPA can also be considered in patients with technically operable disease but in whom the level of vascular obstruction is predominantly distal and in whom the degree of PH or the presence of comorbidities place them at prohibitive risk for a PTE procedure. Further study is needed before BPA is used outside of specialized cardiothoracic centers (see "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy", section on 'Residual pulmonary hypertension' and "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy", section on 'Follow up'). Several small observational studies suggest functional and hemodynamic improvement with BPA [18-28]. As examples:

Patients with inoperable CTEPH – BPA was performed in 68 consecutive patients with inoperable CTEPH [19]. The World Health Organization (WHO) functional class improved from III to II (table 2) and mean pulmonary artery pressure (mPAP) decreased from 45.4 ± 9.6 to 24 ± 6.4 mmHg (5.99 to 3.19 kPa). Forty-one patients developed reperfusion pulmonary injury after BPA, and four of these required transient mechanical ventilation. One patient died of right heart failure 28 days after BPA. BPA, in a French cohort of 184 patients with inoperable CTEPH, resulted in similar improvements and a three-year survival of 95 percent was reported [27]. In a single-center cohort of 138 patients, BPA combined with riociguat resulted in improved survival rates compared with historical controls (100 percent versus 85 percent at one year, 90 percent versus 59 percent at five years) [28].

Residual PH following PTE – In a case series of 308 patients who were not candidates for PTE or had post-endarterectomy residual PH, mPAP improved from 43 to 24 mmHg in response to BPA [26]. The complication rate was 36 percent and mortality was 4 percent. Another preliminary study reported improved functional capacity in 10 patients with residual PH following PTE who were treated with BPA compared with those with residual PH who did not undergo BPA following PTE [25].

Inoperable CTEPH/residual PH following PTE – In pooled data from 29 studies (299 patients with inoperable CTEPH/residual PH following PTE), BPA was associated with improved RV function and size assessed on cardiac magnetic resonance imaging [29].

Factors that influence success or failure are unclear:

Some experts have reported greater success with BPA for discrete ring-like stenosis or web-like lesions [30]. Lesions with total luminal occlusion had the lowest success rate and tortuous lesions were associated with a high complication rate. However, these data need to be replicated before the angiographic appearance of CTEPH lesions can be routinely used to select patients or predict outcome from this procedure.

The presence of underlying renal disease should be taken into consideration, and the potential for contrast-induced nephropathy discussed with the patient, given the amount of contrast required for each procedure (approximately 100 to 300 mL). (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast-associated acute kidney injury related to angiography" and "Patient evaluation prior to oral or iodinated intravenous contrast for computed tomography".)

In patients with severe PH in whom the risk of complications is increased, pulmonary arterial hypertension (PAH) specific medical therapy should be initiated prior to performing the procedure. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy".)

BPA, similar to coronary angioplasty, uses a small catheter to dilate sections of the pulmonary artery significantly affected by thrombus. Repeated sessions are generally required (range is two to eight) with the goal of achieving a reduction in the mPAP. The decision to perform BPA requires a robust experiential base and input from a multidisciplinary evaluative team.

Complication rates vary from 2 to 17 percent and are likely patient-, lesion-, and operator-dependent [31-34]. The risk of reperfusion pulmonary edema associated with percutaneous BPA increases with higher pulmonary arterial pressures. Other complications include pulmonary artery perforation, pulmonary artery dissection, and hemoptysis. (See "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy", section on 'Reperfusion pulmonary edema'.)

Combined therapy — Occasionally, we combine BPA with PH-specific therapy. Preliminary data in patients with inoperable CTEPH suggest that PH-specific therapy with riociguat combined with BPA results in improved functional class and pulmonary hemodynamics [35]. However, this approach has not been compared with PH-specific therapy or BPA alone.

REFRACTORY PATIENTS

Double lung transplantation — Double-lung transplantation is a last-resort option for patients who are not candidates for or who fail pulmonary artery thromboendarterectomy (PTE) and/or balloon pulmonary angioplasty (BPA) and who fail or are not candidates for PH-specific therapy [9]. (See "Lung transplantation: General guidelines for recipient selection".)

The availability of BPA and PH-specific therapy have improved the outcome for patients with inoperable CTEPH, thereby reducing the need for lung transplantation [36].

There are no data on the course of patients with CTEPH following transplantation, compared to patients with other indications for transplantation. (See "Lung transplantation: An overview".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

Introduction – The natural history of chronic thromboembolic pulmonary hypertension (CTEPH) is typically one of progression to right heart failure and death. Selecting patients suitable for pulmonary artery thromboendarterectomy (PTE), which is the only definitive therapy, is a critical step in the management of CTEPH. (See 'Introduction' above.)

Anticoagulation and referral to a CTEPH center

All patients with CTEPH should receive life-long anticoagulation. For all patients with CTEPH, we suggest immediate anticoagulant therapy, provided the risk of bleeding is low (Grade 2C). The rationale for this approach is based upon the biologic rationale that anticoagulant therapy prevents further thromboembolism and indirect data from patients who undergo anticoagulation for acute thromboembolism. For those at high risk of bleeding, we suggest placement of an inferior vena cava filter (Grade 2C) until the bleeding risk is resolved. (See 'Anticoagulant therapy (indefinite)' above.)

-For immediate anticoagulation, intravenous unfractionated heparin, subcutaneous low molecular weight heparin, or a direct oral anticoagulant (DOAC) at therapeutic doses are options and for long term anticoagulation, warfarin or a DOAC may be administered.

-Factors that influence the choice of anticoagulant (table 1) are discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation", section on 'Selection of agent'.)

For all patients with CTEPH, even those with mild symptoms or mild hemodynamic abnormalities, we advocate for early referral to a CTEPH center to ensure optimal outcome from PTE; a delay in referral may result in the development of distal vasculopathy that is not surgically amenable and the opportunity for a cure is lost. (See 'CTEPH center referral' above.)

-The main purpose of the evaluation is to reconfirm the diagnosis of CTEPH, obtain further testing if necessary, and evaluate suitability for PTE.

-The evaluation in specialist centers is undertaken by a multidisciplinary team that reviews data collected during investigation for pulmonary hypertension (PH) and CTEPH. While most PH centers perform pulmonary artery catheterization (PAC) and in some cases, pulmonary angiography, prior to referral, both tests can be readily performed simultaneously at the CTEPH center and as such, are not absolutely necessary for referral. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

Evaluation for pulmonary artery thromboendarterectomy

We evaluate all patients with CTEPH, regarding suitability for PTE (algorithm 1). This is because PTE is the only potentially curative treatment and data support improved pulmonary hemodynamics, functional status, and long-term survival. (See 'Evaluation for pulmonary thromboendarterectomy' above.)

For patients with CTEPH who meet all of the following criteria, we suggest PTE rather than chronic PH-specific drug therapy (Grade 2C):

-Patient has hemodynamically significant PH and/or exercise impairment – The hemodynamic assessment is based upon PAC findings. PH is considered hemodynamically significant if the PVR at rest is in the range of 160 to 1200 dynes-sec/cm-5 (2 to 15 Wood units). For patients whose PVR at rest is <160 dynes-sec/cm-5 (<2 Wood units), we test the pulmonary hemodynamic response to exercise during PAC. If exercise-induced PH is found, PTE is appropriate. For patients without evidence of exercise-induced PH on PAC, the benefits of PTE are less clear; we consider PTE when the patient’s exercise intolerance and/or poor quality of life are such that they are willing to accept the risks of surgery. (see 'Is there significant hemodynamic or exercise impairment?' above)

-Thrombi are surgically accessible – Digital extraction pulmonary angiography (or equivalent) is used to assess whether thromboemboli are surgically accessible. Only proximal thromboemboli (ie, the main, lobar, or segmental arteries) are amenable to PTE while distal disease is not typically surgically accessible. (See 'Are the chronic thromboemboli accessible for surgery?' above.)

-PTE is expected to sufficiently lower the PVR – If it is assessed that the majority of the elevated PVR is due to proximal (ie, surgically accessible) disease, then PTE is more likely to be successful and should sufficiently lower PVR postoperatively. In contrast, if a large component of the elevated PVR is due to distal disease, PTE is less likely to be successful and may lead to poor perioperative outcomes. (See 'What is the anticipated postoperative hemodynamic outcome?' above.)

-Patient is an acceptable candidate for major surgery – PTE is best performed in those at low risk for major thoracic surgery. We assess the risk in a similar fashion to those undergoing other forms of thoracic surgery. (See 'Are there comorbid conditions affecting surgical candidacy?' above and "Evaluation of perioperative pulmonary risk" and "Strategies to reduce postoperative pulmonary complications in adults" and "Evaluation of cardiac risk prior to noncardiac surgery".)

-Patient is willing and motivated to undergo surgery – It is important that the patient and their family are motivated and engaged since patient and caregiver co-operation are very important during the postoperative period. (See 'Are there patient preferences that impact the decision?' above.)

Long-term management

Patients undergoing PTE – For patients who meet the above criteria and undergo PTE, anticoagulation is continued after surgery. We suggest not routinely administering PH-specific therapy as a bridge to surgery (Grade 2C). However, PH-specific therapy may be appropriate for those with profound right heart failure or severe PH who require hemodynamic stabilization in preparation for PTE. (See 'Operable candidates' above and "Chronic thromboembolic pulmonary hypertension: Pulmonary thromboendarterectomy".)

Patients who do not undergo PTE – For patients who are not candidates for or patients who decline or delay PTE, we suggest PH-specific therapy in addition to anticoagulation rather than anticoagulation alone (Grade 2C). While not curative, the available evidence suggests that medical therapy modestly improves exercise tolerance and pulmonary hemodynamics with this approach. For those who fail PH-specific therapy, options include percutaneous balloon pulmonary angioplasty (BPA), or a multimodal approach using a combination of PH-specific therapy and BPA, although data to support these options are less robust. (See 'Inoperable candidates' above and "Chronic thromboembolic pulmonary hypertension: Pulmonary hypertension-specific therapy".)

Refractory patients – For patients with refractory CTEPH who are not candidates for PH-specific therapy and/or BPA or patients who have failed all options (PTE, PH-specific therapy and BPA), evaluation for lung transplantation may be the only option. (See 'Refractory patients' above.)

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Topic 16637 Version 43.0

References

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