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Department of Pulmonology, Academic Medical Center, University of Amsterdam, The Netherlands; Pulmonary Vascular Disease Unit, Papworth Hospital, Cambridge, United Kingdom; Hôpital Antoine Béclère, Clamart, France; and Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
Correspondence and requests for reprints should be addressed to Paul Bresser, M.D., Department of Pulmonology, Academic Medical Center (AMC), P.O. Box 22660, Amsterdam 1100 DD, The Netherlands. E-mail: p.bresser{at}amc.uva.nl
ABSTRACT
Pulmonary endarterectomy (PEA) is recommended as the treatment of choice for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, only a proportion of patients fulfill the criteria for surgical intervention. In addition, operated patients with CTEPH may experience a gradual hemodynamic and symptomatic decline related to a secondary hypertensive arteriopathy in the small precapillary pulmonary vessels. It has also been questioned what can be done to reduce risks from PEA surgery to improve outcome in "high risk" patients with CTEPH with substantial impairment of pulmonary hemodynamics before surgery. Such patients may benefit from preoperative reduction of pulmonary vascular resistance by means of medical therapy. Conventional medical treatments, such as anticoagulation, diuretics, digitalis, and chronic oxygen therapy, show low efficacy in the treatment of CTEPH as they do not affect underlying disease processes. Over the last decade, several novel therapies have been developed for pulmonary arterial hypertension (PAH), including prostacyclin analogs (epoprostenol, beraprost, iloprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase-5 inhibitors (sildenafil). Evidence of efficacy in PAH, coupled with studies showing histopathologic similarities between CTEPH and PAH, provides a rationale to extend the use of some of these medications to the treatment of CTEPH. However, direct evidence from clinical trials in CTEPH is limited to date. This article reviews evidence supporting, and issues surrounding, the possible use of novel PAH medications in CTEPH.
Key Words: bosentan • pharmacotherapy • prostanoid • pulmonary arterial hypertension • thromboembolic
Pulmonary endarterectomy (PEA) surgery can be tremendously effective and often curative in patients with severe chronic thromboembolic pulmonary hypertension (CTEPH) (1), and therefore, represents the treatment of choice for eligible patients (1, 2). However, a substantial proportion of patients with CTEPH is considered inoperable due to significant distal thromboembolic pathology, or is classified as representing poor candidacy for PEA surgery due to concomitant vascular arteriopathy (3–5). Patients in the latter group often suffer from persistent or residual pulmonary hypertension (PH) after PEA (5). As a consequence, mortality after PEA, most often occurring in the early postoperative period, still ranges between 5 and 10% despite improved diagnostic/prognostic assessments and surgical techniques (4). Persistent PH with consecutive right-heart failure, respiratory failure due to pulmonary reperfusion injury, or both conditions together are the main causes of early postoperative death after PEA (1, 5). Although survival in patients with CTEPH who do not undergo surgery has not yet been comprehensively followed up, prognosis in the absence of surgery is very poor, particularly in those with a mean pulmonary artery pressure (mPAP) greater than 50 mm Hg, with 5-yr survival rates as low as 10% in the most severely affected patients (6–9).
In the currently accepted model of the natural history of CTEPH, acute pulmonary embolism (PE), whether symptomatic or asymptomatic, serves as the initiating event after which disease progression occurs. On the basis of a prospective incidence study, Pengo and colleagues (10) estimated that symptomatic CTEPH may affect up to 4% of patients within 2 yr after a first episode of symptomatic PE. CTEPH develops due to progressive pulmonary vascular remodeling and development of a generalized hypertensive pulmonary arteriopathy (5, 11). This has been confirmed at the histopathologic level, with changes in the pulmonary microvasculature in CTEPH appearing very similar to those seen in other forms of severe nonthromboembolic pulmonary arterial hypertension (PAH) (5, 12, 13). As covered in detail elsewhere in this issue (11, 14), operative classifications for assessing PEA candidacy hinge on the balance between PH due to surgically treatable, organized, central obstructions and that due to distal organized thrombi and/or a small-vessel arteriopathy (14). Patients with chronic thromboemboli in distal, inaccessible lung regions are generally considered inoperable (5), although this judgment depends to a degree on the experience of the treating center (1). Patients with significant PH due to pronounced small-vessel arteriopathy, but with little or no visible evidence of thromboembolic pathology, are considered poor candidates for surgery (1, 5, 15, 16).
Medical therapies currently used in the management of post-PE patients come from a number of drug classes (anticoagulants, diuretics, digitalis, calcium channel blockers), but in general do not affect the underlying disease processes of CTEPH. Supportive treatment with anticoagulants reduces the likelihood of recurrent PE, and careful maintenance of lifelong anticoagulation therapy is recommended (17). Diuretics are useful in the treatment of fluid overload, and chronic oxygen therapy provides relief from hypoxemia. Calcium channel antagonists have also been applied in CTEPH, but, as in idiopathic PAH (IPAH), have had only limited success due to the lack of vasoreactivity in the pulmonary vasculature.
Over the past decade, novel therapies have been approved for use in treating IPAH, including prostacyclin analogs (epoprostenol, iloprost), the dual endothelin receptor antagonist bosentan, and the phosphodiesterase-5 (PDE-5) inhibitor sildenafil. The efficacy of these agents in improving pulmonary hemodynamics in IPAH, together with evidence of pathophysiologic mechanisms held in common between IPAH and CTEPH, suggests their potential usefulness in selected patients with CTEPH, especially those with substantial small-vessel arteriopathy. In the following sections, we review evidence assessing the use of novel pharmacotherapies in CTEPH. We look at issues surrounding the place of novel agents alongside conventional treatment, assess the rationales for different pharmacologic approaches, and summarize observations in clinical trials to date.
WHEN IS MEDICAL THERAPY FOR CTEPH APPROPRIATE?
Pharmacotherapy may be beneficial in a number of different situations: (1) where PEA is not suitable due to significant distal thromboembolic disease, (2) as a "therapeutic bridge" to PEA in patients who are considered "high risk" due to extremely poor hemodynamics, (3) in patients with persistent or residual PH after PEA, or (4) when surgery is contraindicated due to significant comorbidity that increases the risk of postoperative mortality. Because much further work is required to establish precisely what type and degree of comorbidity may constitute a contraindication for PEA (scenario 4), we focus in the following sections on scenarios 1 through 3.
Patients with Inoperable Disease
Early PH related to PE often appears to be a direct consequence of obstruction by central organized thrombi (5, 18). Over time, however, gradual hemodynamic and symptomatic decline most likely occurs due to pathology and vascular remodeling in small pulmonary vessels (5, 17). In general, the greater the contribution of distal, surgically inaccessible thrombotic lesions to overall pulmonary vascular resistance (PVR), the higher the risk of perioperative mortality associated with PEA and/or the lower the chance of beneficial hemodynamic improvement after surgery (1, 5). Elevation of pulmonary resistance exceeding that which is attributable to overt mechanical thrombus obstruction is frequently seen, and signals significant and, in some cases, inoperable levels of small-vessel pathology (1, 15).
Pre-PEA "Bridging" Therapy
The concept of introducing medical treatment as a "therapeutic bridge" between CTEPH diagnosis and PEA was initially proposed for continuous intravenous epoprostenol (19, 20). There are two main scenarios where preoperative "bridging" medical therapy may provide benefits. A significant proportion of patients with CTEPH undergoing PEA are hemodynamically unstable in the preoperative period to the point where risks from surgery in general are significantly raised. "High risk" patients can be defined by various criteria: New York Heart Association (NYHA) class IV disease; mPAP greater than 50 mm Hg; cardiac index (CI) less than 2.0 L · min · m–2; PVR greater than 1,000 dyn · s · cm–5. It can be hypothesized that medical therapies demonstrating significant effects on pulmonary hemodynamics in patients with CTEPH may improve surgical success and postoperative outcome by providing control of preoperative pulmonary resistance. However, it is generally agreed that medical therapy should not delay surgical intervention.
A second application of bridging therapy is in cases where the delay to surgery is hazardously prolonged due to limited medical expertise or resources. Treatment to control pulmonary hemodynamics during the waiting period may prove valuable by precluding hemodynamic deterioration. However, a number of clinical management questions remain. What is the optimal period for medical treatment before PEA? With regard to potential beneficial effects on PVR and mPAP, would it be deleterious to suspend surgery to ensure that an "adequate" course of preoperative therapy has been given? Potential benefits of medical therapy in the preoperative period should be carefully balanced so as not to have any negative impact on surgical outcome.
Post-PEA Therapy
Approximately 10 to 15% of patients show persistent PH after PEA surgery (18). As indicated by Dartevelle and colleagues (5), patients with persistent postoperative PH are most likely to be those with morphologic "class IV CTEPH" (according to the criteria proposed by Thistlethwaite and coworkers [21]: i.e., those with probable IPAH associated with distal, small-vessel thrombosis). In patients with significant distal thromboembolic pathology who are considered operable and survive PEA, residual PH can occur, related to pathology that could not be reached during surgery. As discussed in detail elsewhere in this issue (14), recent work with the pulmonary occlusion technique, and subsequent pulmonary artery pressure occlusion waveform analysis, indicates that quantitative preoperative assessments of downstream (small arterial) versus upstream (larger arterial) resistance can help in predicting the risk of persistent postoperative PH (15). Although this technique needs further clinical validation, it may be useful in identifying patients who may benefit from postsurgery medical therapy.
Medical treatment for patients with persistent postoperative PH and consequent hemodynamic instability requires the development of criteria and guidance 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. The same holds true for the group of patients in whom pulmonary hemodynamics do not fully normalize after PEA (i.e., patients with residual PH).
MEDICAL THERAPY: EVIDENCE TO DATE
Data from clinical trials of medical therapy in CTEPH are currently limited and, based on encouraging preliminary trial findings, there is a need to conduct randomized, controlled clinical trials with a number of novel PAH therapies that have already demonstrated efficacy in nonthromboembolic PH (IPAH). For instance, a multicenter, randomized trial ("Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension" [BENEFIT]), which includes a parallel, 4-mo bosentan/placebo-controlled phase, is currently ongoing. In addition, preliminary studies suggest that combining, for example, bosentan or sildenafil with prostanoid therapy may provide further benefits (22–24). In the following sections, we review the relevant published findings in patients with CTEPH.
PROSTACYCLIN ANALOGS
The rationale for the use of prostacyclin analogs in CTEPH is based on current knowledge of the disease pathology and the role of prostacyclin in vasculopathy and the PAH disease process. Prostacyclin is an endogenous substance produced by vascular endothelial cells and induces vasodilatation and inhibition of platelet activity, and has possible antiproliferative effects (19, 25, 26). Prostacyclin metabolic pathways are disrupted in patients with PAH, and prostanoids have been shown to reduce PVR and improve right-ventricular function. Together with evidence of efficacy from clinical trials in IPAH, this provides a rationale for their possible application in CTEPH.
Beraprost Sodium
Ono and colleagues (27) evaluated oral beraprost sodium (BPS) in inoperable patients with distal CTEPH in the absence of major vessel obstruction. Patients were divided into two treatment groups: one receiving oral BPS and conventional therapy (n = 20) versus one receiving conventional therapy alone (n = 23). Overall, improvements in NYHA functional class were observed in 10 patients (50%) after oral administration of BPS. In a subgroup of patients where hemodynamics were evaluated after 2 ± 1 mo of treatment, BPS-treated patients showed significant improvements in mPAP and total pulmonary resistance (TPR), but not cardiac output (Figure 1). Overall, the study suggested that 1- to 5-yr survival may be improved with beraprost therapy in addition to conventional treatment (27).
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Further data were collected in a retrospective study of intravenous epoprostenol given preoperatively for 2 to 26 mo in patients with moderate to severe CTEPH (n = 9) (28). Hemodynamic improvement was observed in some patients with CTEPH before PEA (Figure 2). Six patients experienced either clinical stabilization or improvement, whereas three patients showed clinical deterioration. Substantial improvements in CI, mPAP, and TPR were seen after PEA, but overall, factors predicting beneficial responses to epoprostenol treatment could not be clearly identified (28). Finally, data from a study incorporating a mixed population of patients with PH (16 with IPAH and 11 with surgically untreatable CTEPH) suggested that continuous intravenous epoprostenol therapy, followed up over a median of 12.4 mo, may improve clinical status, exercise tolerance, and NYHA functional class (29).
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ENDOTHELIN RECEPTOR ANTAGONISTS
Endothelins are a family of three endothelium-derived peptides involved in a variety of normal physiologic processes. Endothelin is also one of the most potent and long-lasting endogenous vasoconstrictors (31), and has been shown to play a pathogenic role in PAH. Plasma concentrations of endothelin are increased in patients with CTEPH (32, 33), as are pulmonary endothelin type B receptors on vascular smooth muscle cells (32). Furthermore, endothelin-mediated pulmonary vascular remodeling has been demonstrated in a canine model of CTEPH (34), and pulmonary vascular remodeling distal to pulmonary artery ligation accompanied by up-regulation of endothelin receptors and nitric oxide synthase was shown in a pulmonary ligation model of CTEPH in rats (35).
Bonderman and coworkers (36) assessed the effects of the dual endothelin receptor antagonist bosentan in a series of inoperable patients with CTEPH (n = 16) treated for 6 mo. NYHA functional class improved in 11 patients (
70%). Six-minute walk distance (6-MWD) at 6 mo was significantly improved from baseline (p = 0.01), with parallel reductions in plasma pro-BNP levels (Figure 3).
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3 mo) in patients with CTEPH (n = 20): 15 patients were inoperable due to distal disease, and five had persistent PH after PEA. After at least 3 mo of treatment, significant improvements were seen in 6-MWD (+ 45 m; p < 0.001), PVR, total peripheral resistance, and CI. mPAP was also reduced, but change from baseline did not reach statistical significance, possibly due to variance in treatment durations. More recently, Hughes and colleagues (38) reported findings from a retrospective, open-label study evaluating the long-term efficacy and safety of bosentan in CTEPH at three European centers (n = 47): 39 patients had inoperable CTEPH and eight had persistent PH after PEA. A significant improvement was observed in 6-MWD (52 ± 10 m; p < 0.001) at 1-yr follow-up. Twenty-eight subjects had repeated right-heart catheterization at 1 yr, and there was significant improvement in CI (0.2 ± 0.007 L · min · m–2; p = 0.004) and a decrease in TPR (138 ± 42 dyn · s · cm–5; p = 0.003). Hoeper and colleagues (39) performed a prospective, multicenter, open-label trial evaluating 3-mo bosentan treatment in a mixed population of patients with CTEPH (n = 19). The study population included patients with inoperable CTEPH and patients with persistent or recurrent PH after PEA. After 3 mo of bosentan therapy, PVR had significantly decreased from 914 ± 329 to 611 ± 220 dyn · s · cm–5 (p < 0.001), and 6-MWD increased from 340 ± 102 to 413 ± 130 m (p = 0.009; Figure 4). Significant improvements were also seen in serum pro-BNP levels, mPAP, cardiac output, CI, and systemic vascular resistance.
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PDE-5 INHIBITION
Sildenafil is an inhibitor of PDE-5, an enzyme that is abundantly expressed in the lungs and which stabilizes the second messenger, cGMP, a key mediator in lung vasodilator responses to inhaled nitric oxide and prostanoids (40, 41). Oral sildenafil has been shown to be a potent pulmonary vasodilator (23).
In an open-label study with an approximately 6-mo follow-up, Ghofrani and coworkers (42) assessed sildenafil therapy in patients with CTEPH (n = 12) with nonoperable progressive distal disease and severe PH (PVRI, 1,935 ± 228 dyn · s · cm–5 · m2, and mPAP, 52.6 ± 3.6 mm Hg). Acute vasodilator testing in these patients showed considerable vasoreactivity with both oral sildenafil and inhaled nitric oxide. After 6.5 ± 1.1 mo, 6-MWT and PVR were significantly reduced (Figure 5), and significant changes were also seen in CI, mPAP, and central venous pressure.
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SAFETY ASPECTS
Disease comorbidity (e.g., chronic obstructive pulmonary disease, cardiac disease) is an important factor in the choice of appropriate drug therapy for patients with CTEPH because patients are generally older than those with PAH, and have a greater frequency and severity of comorbidity. It is therefore important to identify any safety issues related to the use of pharmacotherapy in CTEPH, either alone or in conjunction with PEA.
Postmarketing surveillance with bosentan through the Internet-based "Actelion TRAX" system, when set up after observations of elevated liver aminotransferase levels in patients with IPAH treated with bosentan in two pivotal clinical trials, has provided some preliminary information on the safety and tolerability of bosentan for use in CTEPH (44). A total of 4,994 patients were enrolled between May 2002 and November 2004 and, of these, approximately 10% (n = 470) had CTEPH. Median exposure over the 2-yr observation period was 27 wk in patients with CTEPH (up to 122 wk) and 35.4 wk in patients with IPAH (up to 135 wk). Similar safety profiles were seen in CTEPH and IPAH. The frequencies of alanine aminotransferase/aspartate aminotransferase elevations were 8.4% in IPAH and 5.5% in CTEPH. Similar rates of adverse events, hospitalization, and mortality were also seen (44). A single-center study of bosentan-treated patients (n = 149) over 1 yr has recently described a comparable frequency of liver enzyme elevation (12%) in patients with CTEPH (n = 49) compared with IPAH (n = 37) (45).
There are currently no studies specifically reporting on the safety/tolerability of sildenafil therapy in CTEPH, although small studies by Ghofrani and colleagues (42) and Sheth and coworkers (43) indicate no unexpected adverse events or safety issues during 6–24 wk of treatment.
Finally, it is important to consider possible drug–drug interactions between new therapies for PH and medications commonly used in patients with CTEPH. For instance, bosentan has been shown to have a mild CYP3A4-inducing effect, and reductions in warfarin exposure have been observed during concomitant administration with bosentan (46, 47). An increased risk of hypocoagulability has also been suggested in case reports of patients taking sildenafil concurrently with warfarin or acenocoumarol (48), and similar observations have been made with the endothelin A receptor antagonist sitaxsentan (49). Clinical vigilance is clearly necessary with all three agents. In addition, vigilance is required regarding possible drug–drug interactions during combination therapy (discussed below). For instance, sildenafil has inhibitory effects on hepatic CYP3A4, and recent experience with concomitant bosentan therapy showed a possible interaction between these two agents (50).
COMBINATION THERAPY
With the evidence base for significant therapeutic benefits with medical treatment in CTEPH expanding, the use of novel treatments for PH in combination with conventional treatment has grown. Many experts also agree that combinations of prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors will play a major role in therapy in the future. Although reports are yet to be published on clinical experience in CTEPH, there are already published data indicating beneficial hemodynamic effects of combination therapy with bosentan and epoprostenol in IPAH from the "Bosentan Randomized Trial of Endothelian Antagonist Therapy for PAH-2" (BREATHE-2) study (24), and preliminary data suggest beneficial effects with concomitant sildenafil and bosentan treatment in IPAH (22). Sildenafil has also been tested as an adjunctive treatment with prostanoid therapy (inhaled iloprost or continuous intravenous epoprostenol) in IPAH (42, 51, 52). Goal-oriented therapy in PAH with bosentan and/or iloprost and/or sildenafil, given in combination, indicated survival benefits above those seen in a historical control group as well as expected survival calculated using the National Institutes of Health Registry Formula (22). Further studies are required to establish if the benefits of combination therapy seen in PAH extend also to CTEPH.
LIMITATIONS OF CURRENT DATA
To date, the majority of data with medical therapies for CTEPH come from small, uncontrolled studies, retrospective evaluations, as yet unpublished clinical experience, and trials primarily assessing PAH that included, but did not exclusively evaluate, patients with CTEPH. In addition, heterogeneous populations of patients have been assessed using a range of different parameters over variable periods of time, which precludes proper cross-study comparison. Prospective randomized, controlled clinical trials are required that evaluate medical therapy exclusively in patients with CTEPH. The two main methodologic issues that need to be addressed in ongoing and future trials are selection of appropriate target populations and choice of relevant primary and secondary endpoints.
Selection of patients, grouping those with similar stages of disease, will require meticulous diagnostic evaluation since the extent of distal arteriopathy and thromboemboli may not be easy to evaluate in CTEPH. The primary group to assess is patients with inoperable CTEPH, and efforts toward better definition of this population have improved since the introduction of PEA (14). Assessments of medical treatment for patients with persistent or recurrent PH after PEA require a stable clinical condition 3 mo or more after PEA, with no evidence of recurrent thromboembolism. Evaluating medical therapy as a therapeutic bridge to PEA should address cases where surgery at the time of assessment represents an unacceptably high risk due to unstable hemodynamics (e.g., very high PVR). Both pre- and postsurgical outcomes need to be assessed in future studies, with adequate means of defining effects due to medical treatment compared with those due to PEA.
The histology and natural course of CTEPH are similar to those of PAH, and it therefore seems plausible to base clinical trials for CTEPH on trial endpoints already established for patients with PAH. Primary endpoints acceptable for the appraisal of treatment for PAH include the following: exercise capacity, quality of life, time to indices of clinical worsening (e.g., hospitalization, need for epoprostenol or transplant), and mortality. Physiologic parameters, such as hemodynamics, NYHA functional class, and symptom change (e.g., Borg dyspnea index), are considered secondary (reinforcing) endpoints, but are also important to include for a full appraisal of therapeutic effects.
CONCLUSIONS
Although PEA is accepted as the first choice of treatment for CTEPH, evidence is accruing on the potential use of medical therapies alongside surgery and, in some cases, as an alternative treatment strategy. Pharmacotherapy may be particularly useful in treating patients with predominant small-vessel disease who are poor candidates for surgery, or as bridging therapy in those where there is significant preoperative risk. Postsurgery use in controlling persistent or recurrent PH also appears a distinct possibility.
During initial studies, prostanoids, the dual endothelin receptor antagonist bosentan, and the PDE-5 inhibitor sildenafil have all shown potential in the treatment of inoperable CTEPH. Evidence from prospective randomized, controlled clinical trials is required to fully evaluate the clinical effects of novel PAH therapies in CTEPH: trials need to include appropriate patient groups, such as those with surgically inaccessible disease or with pulmonary hemodynamics defined as presenting a high risk for PEA intervention. It is hoped that the ongoing randomized, placebo-controlled trial with bosentan, which includes both inoperable patients and those with residual PH after PEA, will be able to further explore any beneficial effect of medical treatment in CTEPH.
FOOTNOTES
Supported by an unrestricted educational grant from Actelion Pharmaceuticals.
Conflict of Interest Statement: P.B. serves as an advisor to Actelion, and received 
90.000 from Actelion as an unrestricted research grant. J.P.-Z. received honorarium from Actelion, Pfizer, and Schering for speaking at conferences and advisory board meetings. In addition, she holds a joint grant of £75K between Actelion, Pfizer, Lung Rx, and Schering. X.J. has received lecture fees from Actelion. M.H. received support from Actelion, Pfizer, and United Therapeutics for consultancy (Actelion: 2,000 in 2003,2004, 2005); advisory board (Actelion: 2,000 euros in 2003, 2004, 2005, Pfizer: 2000 euros in 2004, and 2005); and lectures (Actelion: 2,000 in 2003, 2004, 2005; Pfizer: 2,000 in 2005; United Therapeutics: 700 in 2005). M.M.H. received honorariums from Actelion Pharmaceuticals and from Pfizer Ltd. for speaking at conferences, consultancies, and advisory board membership. In addition, he received a research grant from Actelion Pharmaceuticals. He received speaker's fees from Schering, Germany.
(Received in original form May 12, 2006; accepted in final form June 19, 2006)
REFERENCES
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|
 |
|
  N. S. Hill, I. R. Preston, and K. E. Roberts Inoperable Chronic Thromboembolic Pulmonary Hypertension: Treatable With Medical Therapy Chest, August 1, 2008; 134(2): 221 - 223. [Full Text] [PDF]
|
|
|
|
|
|
J. Suntharalingam, C. M. Treacy, N. J. Doughty, K. Goldsmith, E. Soon, M. R. Toshner, K. K. Sheares, R. Hughes, N. W. Morrell, and J. Pepke-Zaba Long-term Use of Sildenafil in Inoperable Chronic Thromboembolic Pulmonary Hypertension Chest, August 1, 2008; 134(2): 229 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kearon, S. R. Kahn, G. Agnelli, S. Goldhaber, G. E. Raskob, and A. J. Comerota Antithrombotic Therapy for Venous Thromboembolic Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 454S - 545S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Condliffe, D. G. Kiely, J. S. R. Gibbs, P. A. Corris, A. J. Peacock, D. P. Jenkins, D. Hodgkins, K. Goldsmith, R. J. Hughes, K. Sheares, et al. Improved Outcomes in Medically and Surgically Treated Chronic Thromboembolic Pulmonary Hypertension Am. J. Respir. Crit. Care Med., May 15, 2008; 177(10): 1122 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
M. Lankeit, C. Dellas, A. Panzenbock, N. Skoro-Sajer, D. Bonderman, M. Olschewski, K. Schafer, M. Puls, S. Konstantinides, and I. M. Lang Heart-type fatty acid-binding protein for risk assessment of chronic thromboembolic pulmonary hypertension Eur. Respir. J., May 1, 2008; 31(5): 1024 - 1029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
L. J. Rubin, M. M. Hoeper, W. Klepetko, N. Galie, I. M. Lang, and G. Simonneau Current and Future Management of Chronic Thromboembolic Pulmonary Hypertension: From Diagnosis to Treatment Responses Proceedings of the ATS, September 1, 2006; 3(7): 601 - 607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Peacock, G. Simonneau, and L. Rubin Controversies, Uncertainties and Future Research on the Treatment of Chronic Thromboembolic Pulmonary Hypertension Proceedings of the ATS, September 1, 2006; 3(7): 608 - 614. [Abstract] [Full Text] [PDF]
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