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The Proceedings of the American Thoracic Society 3:601-607 (2006)
© 2006 The American Thoracic Society
doi: 10.1513/pats.200605-111LR
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Current and Future Management of Chronic Thromboembolic Pulmonary Hypertension

From Diagnosis to Treatment Responses

Lewis J. Rubin, Marius M. Hoeper, Walter Klepetko, Nazzareno Galiè, Irene M. Lang and Gérald Simonneau

University of California, San Diego, California; Med. Hochschule Hannover Pneumologie, Hannover, Germany; Vienna Medical University, and University Clinics of Vienna, Vienna, Austria; Istituto di Malattie dell'Apparato Cardiovascolare, Università di Bologna, Italy; and Hôpital Antoine-Béclère, Clamart, France

Correspondence and requests for reprints should be addressed to Lewis J Rubin, M.D., Division of Pulmonary and Critical Care Medicine, University of California, 9330 Campus Point Drive, 7372 La Jolla, CA 92037-1300. E-mail: ljrubin{at}ucsd.edu

ABSTRACT

Although pulmonary endarterectomy (PEA) has been proven a very effective treatment for chronic thromboembolic pulmonary hypertension, it cannot be performed in a substantial proportion of patients. Here, we outline a proposed treatment algorithm, outlining therapeutic alternatives: (1) PEA should be considered as the first treatment option, where possible; (2) medical intervention is a possible option in inoperable patients and those with significant arteriopathy, although only chronic anticoagulation has been widely used to date (advanced medical treatment options could include prostanoids, endothelin receptor antagonists, or phosphodiesterase-5 inhibitors, but randomized clinical trials are required); (3) pulmonary hypertension is likely to persist after PEA in patients with significant small-vessel arteriopathy, resulting in poor clinical outcome and increased perioperative mortality (medical therapy could also be applied here); (4) anticoagulation therapy and, possibly, advanced medical treatment with careful monitoring may provide benefits in patients with mild or asymptomatic disease; (5) if medical therapy begins to fail, PEA should be offered without delay to avoid progression to severe, secondary arteriopathy; (6) in the absence of severe comorbidity, lung transplantation may be undertaken where PEA has failed, in nonresponders to medical therapy, and in patients with progressive arteriopathy; (7) in patients not eligible for PEA due to collateral and/or surgically inaccessible lesions, balloon angioplasty may be a possible alternative at some centers, but is experimental and requires further assessment. Continued research and clinical trials investigating possible applications of new medical treatments are required.

Key Words: angioplasty • medical therapy • pulmonary endarterectomy • pulmonary hypertension • transplantation

Pulmonary endarterectomy (PEA) is the current mainstay of therapy for chronic thromboembolic pulmonary hypertension (CTEPH), although it is a major surgical procedure associated with significant risks, and cannot be performed in a substantial proportion of patients (1, 2). In patients in whom it can be applied, PEA is potentially curative (3–5). However, surgical success is dependent on patient suitability, and there has been much debate and research toward answering two key questions: (1) how do we identify truly inoperable patients? (2) How do we define patients at high risk of surgery failure or perioperative mortality?

Therapeutic approaches other than PEA are currently limited (6). Possible alternatives include lung transplantation and balloon pulmonary dilation (angioplasty). Lung transplantation has been performed successfully in a limited number of patients with CTEPH, although there are specific factors affecting its possible application, and restrictive criteria exist for patient suitability (7). Balloon angioplasty has also been applied in some patients with CTEPH with apparent beneficial effects (6), although this technique requires much further assessment before its routine application can be considered (5).

Conventional medical therapies, including anticoagulants, diuretics, digitalis, and calcium-channel blockers, are already widely used in patients with CTEPH. In particular, data suggest that continuous (life-long) anticoagulation therapy may be beneficial to patients with less severe forms of CTEPH (5, 8). Furthermore, whereas the advent of advanced medical treatments with proven efficacy has brought fresh hope for improved outcomes in patients with non-thromboembolic, idiopathic pulmonary arterial hypertension (IPAH) and secondary PAH, the same may be true for CTEPH. Evidence supporting the rationale of using these pharmacotherapies in CTEPH is growing (9). However, there are currently no data from randomized, controlled, clinical trials specifically assessing medical therapies in CTEPH. Clinical evidence is currently limited to small, uncontrolled trials, and there are a number of questions relating to how advanced medical treatments should be employed alongside surgery in the management of the disease (9). However, a multicenter, randomized trial (BENEFIT), which includes a parallel, 4-mo bosentan/placebo-controlled phase, is currently ongoing.

There is current debate regarding which treatment options are best suited to which patients, and at which time it is best to apply medical and/or surgical treatment in CTEPH. In this article, we look at a number of key issues in the overall clinical management of the disease, and propose a treatment algorithm that may aid in decision-making and improve standardization of patient care.

NATURAL HISTORY AND PATHOPHYSIOLOGY OF CTEPH

The symptomatic history of CTEPH has been well characterized (7, 10, 11). Many patients with CTEPH present late in the course of disease, with progressive exertional dyspnea, hemoptysis, and general clinical deterioration that parallels loss of right ventricular functional capacity. Nonspecific symptoms and lack of medical history of previous thromboembolic disease often complicate accurate diagnosis and, as a result, CTEPH is frequently misdiagnosed and underrecognized in practice (12, 13). The overall occurrence of CTEPH is therefore poorly documented (13), and the early natural history of the condition has not been adequately characterized (14, 15). Nevertheless, studies on CTEPH incidence in post-pulmonary embolism patients (16, 17), and of commonalities between CTEPH and other forms of PAH (15, 18–20), have greatly increased our knowledge of the pathogenesis and long-term progression of the disease.

The weight of evidence suggests that the development of CTEPH is an extension of the natural history of acute pulmonary embolism, although it occurs in only a minority of patients (13). In most patients, the usual natural history seen after pulmonary embolism includes restoration of normal hemodynamics and gas exchange, and total resolution of thromboemboli (or resolution with minimal residuae) within 30 d via mechanical changes in thrombus location and endogenous thrombolysis (12, 21). However, echocardiographic and lung perfusion data indicate incomplete recovery in a substantial proportion of patients who have undergone acute pulmonary embolism, with up to 25% showing persistent pulmonary hypertension (PH) or abnormal lung perfusion patterns up to 1 yr after the event (16, 22, 23). A significant proportion of post-pulmonary embolism patients may therefore be at risk of developing CTEPH.

As covered in detail elsewhere in this issue, there is some speculation on whether CTEPH is purely thromboembolic (24, 25), or whether vascular arteriopathy with local (in situ) pulmonary thrombosis may contribute a large proportion of the raised pulmonary vascular resistance (PVR) and associated PH. This speculation has been fueled by a number of observations, including: differences in risk-factor profiles between patients with pulmonary embolism and those with venous thromboembolism (20, 24, 25); the occurrence of in situ thrombosis in PAH of other etiologies (26, 27); the apparent absence of evidence of venous thromboembolism in many patients with CTEPH (12); differences between the organized thrombotic material removed during PEA from patients with CTEPH and that retrieved during Trendelenburg's embolectomy in acute pulmonary embolism patients (12); and doubts over whether a single or even recurrent pulmonary embolism can produce adequate pulmonary vascular obliteration severe enough to cause PH seen in CTEPH (5). Nevertheless, majority opinion supports the thromboembolic hypothesis of CTEPH pathogenesis, with local thrombosis believed to be involved in stabilization of vascular thrombi, and secondary arteriopathy and vascular remodeling contributing gradual hemodynamic and symptomatic decline (7, 11, 12, 25). As covered elsewhere in this issue (25), it may, therefore, be difficult to distinguish certain patients with distal-type CTEPH (discussed below) from those with PAH and associated in situ thrombosis of peripheral pulmonary vessels, due to the apparent overlap between the two disorders. Current thinking on differential diagnosis for CTEPH has been summarized in detail in other recent articles (5, 28).

CONSIDERATIONS IN APPLYING PEA: CURRENT PERCEPTIONS

PEA is the treatment of choice in patients with a confirmed diagnosis of CTEPH, and can be considered curative, with nearly normalized pulmonary hemodynamics and a substantial improvement in clinical symptoms seen in many patients (3, 4, 7, 29). However, the success of PEA surgery is largely dependent on patient suitability. A careful preoperative assessment is mandatory, and the decision to undertake PEA must be tailored to individual patients based on CTEPH type and, based on experience, the likelihood of successful outcome. Evidence-based clinical guidelines for the application of PEA related to CTEPH have previously been provided by the American College of Chest Physicians (6). However, although extremely important for standardization of patient selection and diagnostics, previous criteria should now be viewed in the context of recent advances in medical therapy for PAH.

Currently, up to 50% of patients with CTEPH may not be suitable for surgery, although this estimate is debatable and varies from center to center: some estimate that the proportion of operable patients may be as high as 80%. To a degree, operability is dependent on the expertise of the surgical team and on the resources available: adequate/extensive experience in PEA is currently limited to only 15–20 centers worldwide. Added to this, we should also consider that, overall, approximately 5–10% of patients experience failure of surgery or nonsustained surgical success (persistent PH and perioperative mortality), although operative failure has decreased substantially over recent years due to increased experience at expert centers (3, 4, 7). Figure 1 summarizes the main factors influencing the decision to operate and outcomes associated with PEA.


Figure 1
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  		Figure 1. Factors considered in assessments of operability for pulmonary endarterectomy.

 
Although useful for research purposes, post hoc (autopsy-based) classification of CTEPH type is of limited use in predicting the outcome of PEA surgery for individual patients. Intraoperative classifications of CTEPH, such as the system introduced by Thistlethwaite and colleagues (30), have been useful in providing information to guide patient management (3, 4, 7). However, a validated system for the detailed, preoperative classification of CTEPH is crucial to enable standardized decision-making for PEA in line with the evolving long-term clinical management of this disease. A possible preoperative assessment system is proposed by Kim elsewhere in this issue (31).

A crucial element in the preoperative assessment of CTEPH, in addition to defining the degree of proximal disease, is the evaluation of microvascular disease (distal organized thrombi and/or small-vessel arteriopathy) and its contribution to overall PVR. Indeed, evaluations of both proximal and distal pathology are considered equally important in decision-making for PEA, particularly with regard to how surgery may be placed alongside other possible interventions, such as long-term medical management (9, 31, 32). Whereas patients with CTEPH with thromboembolic defects at the main, lobar, or proximal segmental level are characterized as having proximal disease and represent the main cases for operability (6, 31), patients with significant PH but with little or no visible evidence of thromboembolic pathology are considered poor candidates for surgery (31, 33). This latter group generally displays a significant mismatch between the degree of proximal obstruction (in radiographic analyses) and the level of hemodynamic impairment (e.g., in terms of PVR).

It is important to establish the best parameters/measurements that allow evaluation of whether distal arteriopathy precludes surgery. For instance, there is some controversy over the use of PVR as a diagnostic guide, although preoperative PVR can be considered at least a marker of prognosis in PEA, and the balance of evidence from several studies indicates that high preoperative PVR has an unfavorable effect on PEA outcome (3, 7, 34, 35). Dartevelle and colleagues (7) observed an almost linear relationship between preoperative PVR and perioperative mortality. However, based on observations of similar operative success in patients with severe hemodynamic impairment compared with those with less pronounced defects, Thistlethwaite and colleagues (30) recently suggested that surgical intervention should not be contraindicated on the basis of preoperative pulmonary artery systolic pressure or PVR.

The identification of true inoperability in terms of proximal versus distal disease, and the definition of high-risk cases (possibly suitable for presurgery medical treatment) remains an issue for further clarification. In the case series reported by Dartevelle and colleagues (7), patients with severely raised PVR were considered operable, although they are likely to make up the bulk of cases showing persistent and/or residual PH after PEA. Post-PEA mortality was related mainly to persistent PH in patients with probable IPAH associated with segmental or subsegmental thrombosis (i.e., "Class IV CTEPH" according to the Thistlethwaite and colleagues [30] classification). This is supported by other studies identifying persistent PH as the main factor contributing to mortality following PEA (3, 34). Patients with inaccessible thromboembolic pathology in distal lung regions were generally considered inoperable (7), although Jamieson and colleagues (3) reported that even obstructions within segmental or subsegmental branches can be removed with adequate experience. Precise cut-off levels are required that identify acceptable degrees of preoperative pulmonary resistance and distal arteriopathy for PEA. Dartevelle and colleagues (7) proposed that patients should be selected for PEA only if a reduction of pulmonary resistance of greater than 50% can be expected.

CONTRAINDICATIONS FOR PEA

Aside from inoperable CTEPH established on the basis discussed above, what are the other contraindications to PEA in CTEPH? There are limited data to evaluate where comorbidity may constitute a contraindication to surgery. Severe underlying chronic lung disease is the only definite contraindication for PEA. Previous evidence-based assessments of the application of PEA in CTEPH (6) have excluded data sets for comorbidities such as severe congestive heart failure, coronary artery disease, or valvular disease, as well as PH associated with congenital heart disease. However, successful outcomes have certainly been seen in patients with these comorbid conditions at some centers (14). There also appears to be no age criterion, with good outcomes reported in patients from 15 to 85 yr of age (14).

There remain questions as to what types/degrees of comorbidity constitute an acceptable risk, whereby PEA can still be performed. Currently, advanced age, concomitant cardiac disease (e.g., coronary artery disease), severe right ventricular failure, renal or hepatic insufficiency and malignancy with reasonable survival expectation are not considered absolute contraindications. However, opinions vary widely, and assessments are currently rather subjective. Further research, definition, and standardization of comorbidity in CTEPH are required, and will help to clarify the situation.

Lack of informed consent also constitutes a contraindication. It is important to consider how information is presented to the patient to ensure that they are in the position to make a "reasonable" and informed decision with regard to the procedure and likely outcomes. Further data and research regarding long-term PEA outcomes and, as discussed below, the possible role of medical therapy in different patient subgroups, will be required in the near future to enable patients to make reasonable, evidence-based decisions.

ISSUES REGARDING MEDICAL THERAPY

Although there is no doubt that eligible patients with CTEPH should undergo PEA, it is currently uncertain how best to manage patients with surgically inaccessible or otherwise inoperable disease. Medical therapies currently used in the management of post-pulmonary embolism patients come from a number of drug classes (anticoagulants, diuretics, digitalis, calcium-channel blockers), but, in general, these medications do not affect underlying disease processes in CTEPH. Current recommended treatment of post-pulmonary embolism patients includes the life-long administration of anticoagulant therapy to reduce the risk of recurrent pulmonary embolism and to restrict the in situ growth of existing chronic obstructions (5, 14). However, a study of prognostic factors in 49 patients with CTEPH, treated only with anticoagulants, reported a 3-yr mortality of 90% in cases with severe PH (pulmonary artery pressure > 30 mm Hg) (8, 36). Nevertheless, a 3-mo period of anticoagulant therapy is currently considered mandatory before PEA is undertaken, to minimize the risk of perioperative pulmonary embolism (4).

Advanced medical therapies that act on relevant underlying mechanisms of disease have been shown to provide functional benefits in PAH (37, 38). Coupled with evidence of a number of common pathogenetic mechanisms and clinical overlaps between non-thromboembolic PAH (IPAH, Eisenmenger's syndrome) and CTEPH (15, 18, 19, 25), studies have begun to evaluate the use of these drugs alongside, or, possibly, as alternatives to, PEA in CTEPH. Among drugs currently approved for the treatment of PAH, therapies that could also be applied in CTEPH include prostanoids (epoprostenol, iloprost), endothelin receptor antagonists (bosentan), and phosphodiesterase-5 inhibitors (sildenafil). Elsewhere in this issue, Bresser and colleagues (9) provide a review of experience with these medications in CTEPH to date. Such medical therapies have been proposed for use in four different scenarios in patients with CTEPH (9):

  1. There is some evidence that the prostacyclin analogs, epoprostenol and beraprost, and the endothelin receptor antagonist, bosentan, can provide benefits in inoperable patients where PEA is not considered applicable due, in most cases, to significant distal thromboembolism (39–44). The evaluation of medical treatment in inoperable disease is the highest priority for assessment in CTEPH, because inoperable patients represent the largest proportion of cases where tangible benefits may be seen.
  2. Pharmacotherapy may help as an adjunctive therapy in patients with persistent or residual PH after PEA, who currently comprise between 10 and 15% of CTEPH cases (21). Patients with persistent postoperative PH are most likely to be those with morphologic "Class IV CTEPH" (according to the classification system of Thistlethwaite and colleagues (30); i.e., probable IPAH associated with distal, small-vessel thrombosis). However, residual PH related to distal (surgically inaccessible) thromboembolic pathology may also occur. The pulmonary occlusion technique, with subsequent pulmonary artery pressure waveform analysis, may be helpful in the future in predicting the risk of postoperative PH, and in defining the population of patients receiving medical treatment under this rationale (33, 45). In addition, guidance will be required on which, how, and when medical therapy should be initiated, particularly for how long it should be continued, and what stopping rules should be applied.
  3. Medical treatment may also benefit patients who are categorized as "high-risk" due to extremely poor hemodynamics, indicating a greater risk of postoperative PH, acting as a "therapeutic bridge" to PEA (46, 47). Alternatively, bridging therapy may be applicable in cases where the delay to surgery is hazardously prolonged due to limited medical expertise or resources. As discussed previously here, further epidemiologic and longitudinal data will be crucial in defining more precisely the classification of high-risk patients. So far, epoprostenol has been assessed for preoperative administration in two studies (47, 48), and iloprost in one study (49).
  4. Medical treatments may be useful where surgery is contraindicated due to significant comorbidity that increases the risk of perioperative mortality. As discussed previously here, further research is required to define precisely which types and degrees of comorbidity will constitute inoperability and, therefore, the population of patients eligible for treatment on this basis.

There is consensus among experts that medical therapy applied as per strategies 1–4 (above) may have a valid role, but that further evidence from randomized, controlled trials is required. A multicenter, randomized trial (BENEFIT), which includes a parallel, 4-mo bosentan/placebo-controlled phase, is currently ongoing. One vital need is for data to set criteria that define patients who are "stabilized" or "deteriorating" with medical treatment. This requires validated cut-offs for efficacy endpoints in terms of time-frame and functional effects. Regarding scenarios 1 and 2, it would be particularly useful to stratify therapeutic trial populations according to these two groups, particularly in assessments of response to treatment. Furthermore, in relation to scenario 2, postsurgery treatment requires effective disease progression monitoring. We therefore need to define strategies/tools to enable the evaluation of meaningful clinical benefits over time. For instance, decreases in plasma brain natriuretic peptide, suggestive of improved right heart function, have been noted in evaluations of epoprostenol bridging therapy (47) and with bosentan in inoperable CTEPH (41, 44). Further data are required to better define the role for such biological disease markers.

Regarding scenario 3, although medical therapy to maintain patients' status before surgery is agreed to be advantageous, therapy that requires unnecessary delay to appropriate surgery may be deleterious. The standard course for anticoagulation therapy is 3 mo, and, in some cases, this may be a dangerous delay. In general, it is believed that such a course of pretreatment should be applied only in nondeteriorating patients, and the same may be true in applying advanced medical therapy. It is also pertinent to note that some degree of tissue alteration may occur with prolonged medical therapy, and this may affect operability. For instance, increased fragility of thromboemboli has been noted following as little as 2 wk of treatment with prostacyclins. This fragility may contribute adverse effects on operability and surgical outcome.

TRANSPLANTATION AND BALLOON ANGIOPLASTY

Current evidence-based guidelines cite lung transplantation or balloon angioplasty as a possible option in patients with CTEPH deemed inoperable for PEA or with significant residual postoperative PH (6). A number of challenges exist related to lung transplantation (e.g., number of donors vs. demand, life-long immunosuppression, chronic infection risk), but there are specific factors affecting outcome in CTEPH. For example, the risk of complications is higher in patients who have already undergone PEA and have shown incomplete success. Restrictive criteria for recipient selection also need to be applied, such as life expectancy less than 1 yr, consistent with New York Heart Association (NYHA) functional status Class III or IV, or recent worsening to severe dyspnea or hemodynamic impairment (7). Overall post-transplant mortality rates in CTEPH transplant recipients have been reported as approximately 20%, regardless of transplantation type (unilateral, bilateral, or combination [heart-lung]), with the 5-yr actuarial survival rate estimated at approximately 50% (7).

Balloon angioplasty can also be applied in some patients where PEA is not an option, although the current evidence base indicates limited benefits (6). Some improvements in 6-min walk distance and NYHA functional class have been seen in patients with distal thromboembolism selected according to specific operative criteria (e.g., complete proximal pulmonary vascular occlusion, filling defects, and intravascular webs). However, expertise with this technique in CTEPH is currently very limited worldwide (6, 50). From a surgical perspective, angioplasty is considered unlikely to have a valid role. It can be associated with all the problems of full surgery (as in PEA), and so may be dangerous to apply in patients who are not considered good candidates for PEA. Nevertheless, as with PEA, it is interesting to speculate on how balloon angioplasty may fit in against cotreatment with advanced medical therapies. Further research in carefully defined patient groups is needed to define an overall treatment pathway incorporating this strategy.

OVERALL DISEASE MANAGEMENT ISSUES

Experts agree that there is a strong need for greater standardization of a number of factors in the management of CTEPH: diagnostic techniques; resource availability; interdisciplinary referral lines; preoperative classification and surgical intervention criteria; PEA techniques and instrumentation; and postoperative management. Possible schemes for enhanced diagnosis, monitoring of disease progression, and assessments of operability are discussed in detail elsewhere in this issue (28, 31). With increasing knowledge of risk factors, predisposing medical conditions, and the number of diagnostic and treatment aspects involved in CTEPH, it is becoming increasingly clear that the optimal management of the condition, both now and in the future, requires effective multidisciplinary interaction within a standardized framework of diagnosis, preoperative assessment (operability), medical therapy, and disease progression monitoring. This system involves numerous medical specialties, including cardiology, surgery, pulmonary medicine, radiology, critical care, and anesthesiology. Information sharing between different groups/centers, in particular between pulmonologists, radiologists, and surgeons, will be a key factor in disseminating "personal experience" information.

A PROPOSED TREATMENT ALGORITHM FOR THE CLINICAL MANAGEMENT OF CTEPH

Figure 2 summarizes a proposed treatment algorithm for implementation as a recommended system of assessment, referral, and management of CTEPH within the multidisciplinary team framework outlined previously here. PEA, medical treatment, transplantation, and, possibly, angioplasty are placed alongside each other in an experience-based decision tree. Overall, a hierarchical breakdown of main points can be summarized as follows:

  1. PEA should be considered as the first treatment option, where possible. Current basic criteria for the application of PEA include: (1) NYHA functional Class III or IV symptoms; (2) a preoperative pulmonary vascular resistance of greater than 300 dyn · s · cm–5; (3) surgically accessible thrombus in the main lobar or segmental pulmonary arteries; and (4) no severe comorbidities (6).
  2. Medical intervention is an option in inoperable patients and those with significant arteriopathy, although, until now, only chronic anticoagulation has been widely used, and randomized, controlled clinical trial evidence with advanced therapies is unavailable. However, a multicenter, randomized trial (BENEFIT), which includes a parallel, 4-mo bosentan/placebo-controlled phase, is currently ongoing.
  3. PH is likely to persist after PEA in patients with significant pulmonary arteriopathy, resulting in poor clinical outcome and increased perioperative mortality.
  4. Anticoagulation therapy and, possibly, advanced medical treatments may provide benefits in patients with mild or asymptomatic disease, but should be administered with careful monitoring.
  5. If medical therapy begins to fail, PEA should be offered without delay to patients without severe comorbidity in order to avoid progression to severe, secondary arteriopathy.
  6. In the absence of severe comorbidity, lung transplantation may provide a further option in cases where PEA has failed, for those who do not respond adequately to medical therapy, and in patients with progressive arteriopathy.
  7. In patients not eligible for PEA due to the presence of collateral and/or surgically inaccessible lesions, balloon angioplasty has been suggested as a possible alternative at some centers, but is considered experimental and requires further assessment.


Figure 2
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  		Figure 2. A proposed, preliminary treatment algorithm for classic bilateral chronic thromboembolic pulmonary hypertension. Medical treatment refers to prostanoids, endothelin receptor antagonists, or phosphodiesterase-5 inhibitors; severe comorbidity currently refers to concomitant severe chronic pulmonary disease.

 
There are a number of areas that require further research and input before this system is properly validated. As previously discussed here, the definitions of "operability" and "high-risk" patients are a major challenge, and further clarification of the types and degree of comorbidities that do not preclude surgery is necessary. Uniform criteria are required to define "significant" hemodynamic/ventilatory problems (e.g., PVR mildly to moderately elevated with symptoms). Further pharmacotherapy trials need to define "stabilization" and "deterioration" with medical treatment. The debatable issue of applying balloon angioplasty in patients with severe comorbidity (with or without concomitant medical treatment) requires detailed attention. Finally, it may be advantageous to list comorbidities (e.g., significant left ventricular dysfunction) that routinely affect surgical decision-making within a finalized algorithm.

CONCLUSIONS

Although PEA is the mainstay treatment for CTEPH and should be considered as the first-line therapy, it is not sufficient to address the needs of all patients. Recent years have seen significant strides in knowledge on the natural history and pathogenesis of CTEPH, and we now need to reassess treatment strategies in order to optimize long-term therapeutic outcomes. Overall, there is an absolute requirement for a multidisciplinary approach at all stages of CTEPH care management.

Transplantation, balloon angioplasty, and, in particular, advanced medical therapies represent possible alternatives to PEA in CTEPH. Medical therapy also fills possible adjunctive roles alongside PEA. There is consensus among experts that medical therapy may be important in a significant proportion of patients with CTEPH, but that further studies and careful monitoring of disease progression during prolonged therapy are required. More information is also required to define how best to place medical treatment alongside other treatment modalities. Pulmonary transplantation represents a last-resort option for patients with inoperable disease that are unresponsive to medical treatment. In the absence of substantial clinical evidence, balloon angioplasty appears to have a limited role in CTEPH, but may provide an alternative for patients who are strictly categorized as not suitable for PEA.

The development of an effective, validated tool for standardized preoperative selection of patients who will gain appreciable benefit from surgery is an important priority (discussed by Kim elsewhere in this issue) (31). Standardized methods of predicting surgical outcome and the degree of secondary arteriopathy are also expected to prove beneficial. The treatment algorithm proposed here was favored by the majority of expert participants in an International Advisory Board meeting. However, the criteria at each branch point require further definition.

FOOTNOTES

Supported by an unrestricted educational grant from Actelion Pharmaceuticals.

Conflict of Interest Statement:L.J.R. has served as a consultant and Advisory Board member for Actelion, for which he has received compensation of $25,000 annually for the past 4 years. He is a co-investigator in an Actelion-sponsored study of Bosentan in CTEPH. M.M.H. received honorariums from Actelion Pharmaceuticals and from Pfizer Ltd. for speaking at conferences, consulting, and Advisory Board membership. In addition, he received a research grant from Actelion Pharmaceuticals. He received speaker's fees from Schering, Germany. W.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.G. has received fees for Advisory Boards by Pfizer ($2,000), Actelion ($3,000), Encysive ($1,500), Myogen ($1,500), and MondoBIOTECH ($5,000). He has received lecture fees paid by Actelion ($2,500) and Schering ($1,500). The Institute of Cardiology of the University of Bologna, where he is employed, has received research grants for participating in multicenter clinical trials by Pfizer ($20,000), Schering ($10,000), Encysive ($15,000), Actelion ($20,000), and Myogen ($20,000). I.M.L. has received {euro}2,000 from Actelion for participation in a scientific meeting. She has been paid {euro}750 for participating in an Actelion Advisory Board meeting in Austria. G.S. reports having received consulting and lecture fees from Actelion ($15,000/yr), Schering ($10,000), Pfizer ($7,500/yr), United Therapeutics ($15,000/yr), and Encysive ($3,000/yr).

(Received in original form May 10, 2006; accepted in final form May 31, 2006)

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