Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
21, 2018
Chronic Thromboembolic
Pulmonary Hypertension
Evolving Therapeutic Approaches for Operable and
Inoperable Disease
Ehtisham Mahmud, MD,a Michael M. Madani, MD,b Nick H. Kim, MD,c David Poch, MD,c Lawrence Ang, MD,a
Omid Behnamfar, MD,a Mitul P. Patel, MD,a William R. Auger, MDc
ABSTRACT
Chronic thromboembolic pulmonary hypertension (CTEPH), a rare consequence of an acute pulmonary embolism, is a disease
that is underdiagnosed, and surgical pulmonary thromboendarterectomy (PTE) remains the preferred therapy. However,
determination of operability is multifactorial and can be challenging. There is growing excitement for the percutaneous
treatment of inoperable CTEPH with data from multiple centers around the world showing the clinical feasibility of balloon
pulmonary angioplasty. Riociguat remains the only approved medical therapy for CTEPH patients deemed inoperable or with
persistent pulmonary hypertension after PTE. We recommend that expert multidisciplinary CTEPH teams be developed at
individual institutions. Additionally, optimal and standardized techniques for balloon pulmonary angioplasty need to be
developed along with dedicated interventional equipment and appropriate training standards. In the meantime, the
percutaneous revascularization option is appropriate for patients deemed inoperable in combination with targeted medical
therapy, or those who have failed to benefit from surgery. (J Am Coll Cardiol 2018;71:2468–86) © 2018 The Authors.
Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Manuscript received December 3, 2017; revised manuscript received March 19, 2018, accepted April 3, 2018.
endogenous fibrinolysis, fibrin variants resistant to such as cardiomyopathy, ischemic heart dis- AND ACRONYMS
intrinsic fibrinolysis, and in situ thrombosis due to ease, and obstructive or restrictive pulmonary
BPA = balloon pulmonary
pulmonary arteriopathy rather than a thromboem- disease, are typically suspected (24,27). Chest angioplasty
bolic basis for disease (14–16). Deficient angiogenesis radiography and pulmonary function tests
CBCT = cone beam computed
and inflammation have similarly been suggested as are helpful in excluding possible airway or tomography
playing a role in disease evolution (17). Inflammatory parenchymal lung diseases; electrocardiog- CT = computed tomography
markers such as C-reactive protein and tumor necro- raphy may demonstrate findings associated CTED = chronic
sis factor alpha are elevated in CTEPH, and the pres- with pulmonary hypertension or other cardiac thromboembolic disease
ence of inflammatory cytokines also suggests that disorders (28–30). For those patients with CTEPH = chronic
failure in endogenous fibrinolysis and thrombus suspected pulmonary vascular disease as thromboembolic pulmonary
hypertension
breakdown could be a consequence of an inflamma- described in the preceding text, additional
LAO = left anterior oblique
tory process (18–20). Other infrequent conditions and evaluative studies need to be considered.
clinical disorders associated with the development of To screen for pulmonary hypertension and mPAP = mean pulmonary
artery pressure
CTEPH include ventriculoatrial shunt, pacemaker right heart dysfunction, transthoracic echo-
PAH = pulmonary arterial
presence, previous splenectomy, a myeloproliferative cardiography should be obtained (31). Doppler
hypertension
disorder, and the presence of chronic inflammatory estimate of right ventricular systolic pressure,
Pd/Pa = mean distal to
disorders such as inflammatory bowel disease and right ventricular and atrial chamber size and proximal arterial pressure ratio
osteomyelitis (21–23). function, and interventricular septal motion PTE = pulmonary
are features discernible with this noninvasive thromboendarterectomy
CLINICAL PRESENTATION
imaging modality. An echocardiogram pos- PVR = pulmonary vascular
sesses the additional value in assessing resistance
Patients with CTEPH often present with progressive
whether there is valvular or left heart disease, RPE = reperfusion pulmonary
dyspnea, exercise intolerance, and nonspecific ab- edema
either as a comorbid condition or as the
normalities on physical examination. As the disease UC = University of California
possible alternative etiology of pulmonary
progresses, there is a high risk of developing pulmo-
hypertension. Diagnostic algorithms (25,32) V/Q = ventilation/perfusion
nary hypertension and right heart failure. Patients
recommend ventilation/perfusion (V/Q) lung imaging
frequently have New York Heart Association func-
as a pivotal screening test in the evaluation of CTEPH
tional class III to IV symptoms (7) and may exhibit
patients (Table 2, Figure 1).
signs and symptoms of right ventricular hypertrophy
or failure, such as jugular venous distension, right
LUNG VENTILATION-PERFUSION SCINTIGRAPHY.
ventricular lift, fixed splitting of the S2 heart sound,
V/Q lung imaging is the initial screening test for
right ventricular S3, exertional angina, syncope,
evaluating patients with pulmonary hypertension
hepatomegaly, ascites, and peripheral edema (10,24).
suspected of CTEPH (3,10,24). V/Q scanning is
The natural history of acute pulmonary embolism is
highly sensitive (96% to 97.4%) in detecting
resolution of emboli within 3 to 6 months in patients
perfusion abnormalities and therefore suggesting
receiving antithrombotic therapy. Therefore, persis-
the possibility of CTED. Furthermore, with its
tent signs and symptoms after this period of anti-
negative predictive value of nearly 100%, a normal
coagulation therapy might signal the presence of
V/Q scan excludes the diagnosis of CTEPH (33).
chronic thromboembolic disease (CTED), and an eval-
Nonetheless, despite the value of lung scintig-
uation for such is warranted (25). However, CTEPH is
raphy, V/Q scan is under-utilized and data from
often diagnosed at an advanced stage due to nonspe-
the PAH-QuERI (Pulmonary Arterial Hypertension
cific symptoms and late appearance of more specific
Quality Enhancement Research Initiative) registry
signs (26). In the European CTEPH registry, it was
demonstrate that only 57% of pulmonary arterial
observed that over a year (median 14.1 months) passed
hypertension (PAH) patients undergo V/Q imaging
from the time of clinical presentation to diagnosis (27).
to exclude CTEPH during their evaluation (34).
Data from the same registry revealed that 74.8% of
However, the nonspecificity of this modality limits
patients with CTEPH reported a previous history of
its utility for the diagnosis of CTEPH, and any
acute pulmonary embolism, whereas only 56.1% had a
abnormal perfusion scan requires additional diag-
history of deep venous thromboembolism (27).
nostic imaging. Computed tomographic pulmonary
DIAGNOSIS angiography, magnetic resonance imaging, and/or
catheter-based pulmonary angiography are ulti-
The diagnosis of CTEPH solely based on history and mately required to establish the diagnosis of
physical examination findings is challenging, and CTED.
2470 Mahmud et al. JACC VOL. 71, NO. 21, 2018
4 frames/s during contrast injection, then decreased to CTEPH. A normal scan virtually excludes the diagnosis while an abnormal scan requires
additional diagnostic tests including invasive hemodynamic and angiographic evaluation.
1 frame/s during the levophase. Angiographic imaging
CT ¼ computed tomography; CTE ¼ chronic thromboembolism; CTEPH ¼ chronic
is often prolonged to record levophase pulmonary vein thromboembolic pulmonary hypertension; ECG ¼ electrocardiogram; mPAP ¼ mean
drainage and exclude pulmonary vein stenosis or pulmonary artery pressure; PCWP ¼ pulmonary capillary wedge pressure.
anomalies.
Characteristic pulmonary angiographic findings
type B, web lesion; type C, subtotal lesion; type D,
suggestive of CTEPH include webs or bands, intimal
total occlusion; and type E, tortuous lesion (49)
irregularities, pouch defects, abrupt vascular nar-
(Figure 4).
rowing, and complete obstruction of pulmonary
arteries (48) (Figure 3). Though in the past, selective MANAGEMENT OF OPERABLE CTED
pulmonary angiography of individual pulmonary
artery segments was unnecessary for identifying Both American and European guidelines endorse
CTED and determining surgical candidacy, the surgical therapy in all patients who have accessible
evolving success of distal vessel thromboendarter- disease and are considered suitable surgical candi-
ectomy and the availability of balloon pulmonary dates (24,25). Surgery by means of a complete bilat-
angioplasty has revived the value of this technique. eral pulmonary thromboendarterectomy offers the
With this, a new classification of lesion morphology best chance of improved long-term outcomes. At
based on the lesion opacity and the blood flow distal experienced centers, disease at segmental and even
to the lesion on pulmonary angiographic images has subsegmental branches can be removed. After the
been described, as follows: type A, ring-like stenosis; introduction of the procedure at the University of
2472 Mahmud et al. JACC VOL. 71, NO. 21, 2018
(A) Abrupt vascular narrowing with intimal irregularity of the right interlobar artery (white arrow). (B) Early contrast phase showing rounded
vascular irregularity, “pouch defect” consistent with recanalized thrombus. (C) Web defect and vessel narrowing (open arrow) of the left
descending pulmonary artery. (D) Value of lateral angiogram: lateral view (LAT) clearly defining the occlusion of the right descending pul-
monary artery beyond the superior segment take off. CTEPH ¼ chronic thromboembolic pulmonary hypertension; PA ¼ posterior-anterior
view.
distal segmental or subsegmental arteries are more area of the vessel and carefully extended until the
likely to be deemed technically inoperable than those diseased areas distally in the segmental and sub-
with more proximal disease. In such patients, the segmental branches are encountered and removed.
plane of dissection is started proximally in the normal This can be challenging because the normal intima is
2474 Mahmud et al. JACC VOL. 71, NO. 21, 2018
(A) Type A: ring-like stenosis lesion. (B) Type B: web lesion. (C) Type C: subtotal lesion. (D) Type D: total occlusion lesion. (E) Type E: tortuous
lesion. Type A–D lesions (arrows) are located proximal to the subsegmental pulmonary artery, namely, the segmental and subsegmental
arteries. Type E lesions (arrowheads) are located distal to the subsegmental artery. CTEPH ¼ chronic thromboembolic pulmonary hyper-
tension. Reprinted with permission from Kawakami et al. Circ Cardiovasc Interv 2016;9:e003318 (49).
Bilateral pulmonary endarterectomy with resection of proximal level I disease with associated diagnostic pulmonary angiograms. PTE ¼ pulmonary thromboendar-
terectomy. (Online Video 1) Distal vessel pulmonary thromboendarterectomy. The dissection plane between the intimal and medial layers of the proximal pulmonary
artery is identified and the dissection extended distally to the occluded segment. Following this, the chronic thromboembolic material is removed.
JACC VOL. 71, NO. 21, 2018 Mahmud et al. 2475
MAY 29, 2018:2468–86 Chronic Thromboembolic Pulmonary Hypertension
Surgical resection of proximal to more distal level of disease in CTEPH patients. Technically, level III to IV disease is more challenging to resect
but results in hemodynamic and clinical improvement; however, resection is associated with higher complications. CTEPH ¼ chronic
thromboembolic pulmonary hypertension.
quite fragile and difficult to dissect free. In cases the corresponding lung. It is important to note that
where the obstructive material is visible distally, an this is a surgical classification as encountered at the
experienced surgeon may start the plane of dissection time of endarterectomy. As imaging modalities
at the segmental level. The goal is to ensure that all improve, the ability to predict the level of disease
thromboembolic material is removed, and all the pre-operatively has improved; however, invariably
branches have been cleared, before restarting the more disease is encountered at the time of surgery
circulation. than predicted on routine imaging pre-operatively.
A recent intraoperative classification of the disease Notably, greater technical expertise is required for
(levels I to IV) (Figure 6) suggested by the UC San level III to IV disease resection with higher compli-
Diego group categorizes pulmonary thromboembo- cations, but hemodynamic improvement can still be
lism in CTEPH as levels, based on the location of the expected after successful surgery.
fibrotic thromboembolic material: level 1, involving Historically accepted indications for PTE were
the main pulmonary arteries; level 2, starting at the a mean pulmonary artery pressure (mPAP)
lobar branches; level 3, starting at the segmental >30 mm Hg, pulmonary vascular resistance (PVR)
branches; and level 4, where disease is only encoun- >300 dynes ∙ s ∙ cm 5, and New York Heart Asso-
tered at the subsegmental branches. In addition, ciation functional classification of III to IV (54,55).
Level 1C indicates complete occlusion of 1 lung with However, it is also presently indicated for patients
total obstruction of the main right or left pulmonary with symptomatic CTED who are dyspneic or
artery, and level 0 indicates no evidence of CTEPH in develop pulmonary hypertension only with exercise.
2476 Mahmud et al. JACC VOL. 71, NO. 21, 2018
C ENTR AL I LL U STRA T I O N CTEPH Treatment Algorithm by the Multidisciplinary UC San Diego CTEPH Team
Once the diagnosis of CTEPH is confirmed, patients are evaluated for PTE surgery. In cases deemed to be to be inoperable, with persistent symptomatic pulmonary
hypertension after PTE surgery, or with an unacceptable risk-benefit ratio, targeted medical therapy and/or BPA is considered. Often patients undergo combined
medical therapy and BPA for optimal hemodynamic and clinical results. BPA ¼ balloon pulmonary angioplasty; CTEPH ¼ chronic thromboembolic pulmonary
hypertension; PTE ¼ pulmonary thromboendarterectomy; UC ¼ University of California.
improved 3-year survival rates compared with those improvement in functional class, remodeling of the
not undergoing surgery (27). Other benefits that right ventricle resulting in reduced wall thickness,
are typically observed include improvements in he- increased right and left ventricular ejection fractions,
modynamic parameters (reduction in PVR and mPAP), and reduced volumes (51,71,72).
2478 Mahmud et al. JACC VOL. 71, NO. 21, 2018
The baseline and final left lower lobe A8 (lateral), A9 (middle), and A10 (medial) segment balloon pulmonary angioplasty (BPA) at a single
treatment session. All 3 segments were occluded and recanalized with 2.0- to 4.0-mm diameter balloons.
JACC VOL. 71, NO. 21, 2018 Mahmud et al. 2479
MAY 29, 2018:2468–86 Chronic Thromboembolic Pulmonary Hypertension
Serial balloon pulmonary angioplasty (BPA) was performed in a right lower lobe A8 segment. An initial angiogram (top row, left image) showed diminished upper
branch distal perfusion and lower branch subtotal occlusion. Intravascular hemodynamics (bottom row) were notable for elevated baseline pulmonary artery (PA)
pressure (systolic >60 mm Hg, mean 35 to 40 mm Hg), significantly dampened distal pressure waveform (upper branch), and resting Pd/Pa ratio <0.50. BPA using
2.0-mm and 3.0-mm balloons resulted in immediately improved upper vessel perfusion by angiography (top row, right image) and intravascular hemodynamics (distal
pressure waveform and Pd/Pa >0.50). A repeat procedure 2 months later showed improved angiographic appearance of both A8 branches (middle row, left image),
PA pressure (systolic 50 mm Hg, mean <30 mm Hg), distal pressure waveform (systolic 20 to 25 mm Hg), and resting Pd/Pa >0.60. Repeat BPA using a 4.0-mm
balloon in both branches resulted in immediately improved distal pressure (systolic 25 to 30 mm Hg) and Pd/Pa >0.65. Final angiography following kissing balloon
inflation showed improved flow within both branches. Pd/Pa ¼ mean distal to proximal arterial pressure ratio (purple line).
inoperable CTEPH. In the macitentan-treated group, distance increased in the macitentan-treated group
PVR decreased to 73.0% of baseline, whereas PVR by 35 m compared with an increase of only 1 m in the
decreased to 87.2% of baseline (p ¼ 0.041) in the placebo-treated group. Important distinctions must
placebo-treated group. At 24 weeks, 6-min walk be made between the methods of this study and the
2480 Mahmud et al. JACC VOL. 71, NO. 21, 2018
CHEST-1 study. The MERIT (Macitentan for the PERCUTANEOUS INTERVENTIONAL THERAPY
Treatment of Inoperable Chronic Thromboembolic
Pulmonary Hypertension) study was smaller in size, Balloon pulmonary angioplasty (BPA), also known as
included only patients who were inoperable, and percutaneous transluminal pulmonary angioplasty,
permitted the use of background PAH therapy (61% of was initially studied as an alternative treatment for
the patients also using PDE-5 or oral/inhaled prosta- selected patients with inoperable CTEPH almost 2
cyclin) (76). decades ago (83,84), but the approach was abandoned
BENEFIT (Bosentan Effects in iNopErable Forms of due to the frequency of major complications. Over the
chronIc Thromboembolic pulmonary hypertension), a past 5 years, the procedure has undergone refinement
double-blind, randomized, placebo-controlled study with promising outcomes and safety data from
of the endothelin receptor antagonist, bosentan, in various centers around the world. Contemporary BPA
inoperable or persistent/recurrent pulmonary hyper- aims to disrupt organized, flow-limiting obstructions
tension after PTE demonstrated a reduction in PVR by and improve pulmonary vascular blood flow.
24% in the bosentan-treated group compared with Unlike coronary artery and peripheral vascular in-
placebo (95% confidence interval: 31.5% to 16.0%; terventions, where symptomatic relief can be expe-
p < 0.0001) at 16 weeks (77). However, the trial failed rienced after revascularization of a single vessel,
to demonstrate a difference in 6-min walk distance at clinical improvement following BPA is typically
16 weeks, which was a coprimary endpoint. There is observed after revascularization of multiple diseased
no obvious explanation for the differences observed segments and regions. In recognition of the success of
in the outcomes between the BENEFIT and MERIT BPA, the 2015 European Society of Cardiology/Euro-
trials and could include trial size, design, and prop- pean Respiratory Society guidelines for the diagnosis
erties of the specific endothelin receptor antagonist and treatment of pulmonary hypertension have rec-
studied. Other PAH-targeted therapies, including ommended BPA in CTEPH patients who are techni-
prostacyclins and PDE-5 inhibitors, have shown some cally inoperable or carry an unfavorable risk-benefit
benefits in small case-controlled studies or subgroups ratio for PTE (recommendation Class IIb, Level of
of larger PAH randomized controlled trials (78–82). Evidence: C) (25).
However, the subgroup of PTE patients pre-treated BPA has been performed in the majority of
with PAH therapies had no significant advantage patients for symptomatic, inoperable CTEPH (85–93)
over those without medical therapy. Instead, the or for persistent/recurrent pulmonary hypertension
medically treated group had a significant time delay following PTE (94–96). Rescue BPA has also been re-
in referral for surgery compared with the rest. ported as a transitional or bridging treatment option
JACC VOL. 71, NO. 21, 2018 Mahmud et al. 2481
MAY 29, 2018:2468–86 Chronic Thromboembolic Pulmonary Hypertension
be addressed by a thin bioresorbable scaffold The combined approach of pressure wire guidance
developed for this vascular bed. to measure gradients across stenosis and the Pulmo-
F u n c t i o n a l a s s e s s m e n t . Prediction of obstructive nary Edema Predictive Scoring Index might be useful
pulmonary artery disease is difficult by angiography in reducing the risk of RPE and vascular complica-
alone, and relatively normal-appearing vessels within tions (100). This approach to finishing each BPA ses-
pulmonary segments underperfused by noninvasive sion using the scoring index with the goal of
imaging warrant intravascular functional assessment scores <35.4 and the guidance of pressure wire to
(Figure 8). Measuring distal pressure using a achieve a distal mean pulmonary arterial
microcatheter-based manometer (Navvus Micro- pressure <35 mm Hg in each target lesion resulted in
Catheter, Acist, Eden Prairie, Minnesota) that can be similar hemodynamic improvements as BPA without
advanced over any guidewire is an effective strategy. this guidance, but was associated with fewer numbers
There is no standardized protocol or numerical cut- of BPA procedures and treated target lesions, and
point for pressure measurement or subsequent ther- absence of RPE. However, no definitive data exist to
apy. In 1 study, the BPA procedure was continued support this approach.
with the aim of achieving a mean distal to proximal Pulmonary artery perforation/rupture is a serious
arterial pressure ratio (Pd/Pa) >0.80 unless the complication of BPA and is reported in 0% to 7% of
baseline mPAP was >35 mm Hg (100). Investigators procedures (86–88,103). Some measures suggested
reported a very low rate of procedure-related adverse to decrease the risk of pulmonary artery perforation
events using this strategy and were able to avoid RPE include proper wire positioning, knuckle-wire tech-
in the majority of patients. Our strategy has been to nique, appropriate balloon sizing, and avoidance of
use a Pd/Pa ratio for treatment guidance with occluded segments without distal flow (99). Nonin-
values <0.75 prompting additional balloon dilation vasive positive-pressure ventilation with supple-
(larger balloons, higher pressures, or scoring bal- mental oxygen, and in more severe situations
loons/guidewires). Frequently, the ratio only changes mechanical ventilation and extracorporeal mem-
marginally and improves over time. Interval nonin- brane oxygenation, should be considered as the first
vasive perfusion scans between therapy sessions are therapeutic strategy for severe lung injury or
also useful to evaluate perfusion within treated seg- vascular rupture following BPA to maintain
ments and support repeat intervention for areas with oxygenation and preserve blood pressure (104).
persistent hypoperfusion. Immediate balloon tamponade of the perforated/
ruptured vessel, cessation/reversal of anti-
COMPLICATIONS OF BPA. In recent series, BPA coagulation, covered stent implantation, Gelfoam
periprocedural mortality ranged from 0% to 10% (85– injection, and transcatheter coil embolization are
93). The 2 most common complications of BPA suggested bailout techniques in these situations
include RPE and pulmonary vascular injury, with rare (87,104).
episodes of vessel perforation/rupture. Despite the
advances and improvement of the procedure, RPE CLINICAL OUTCOMES OF BPA. In the short term, the
remains a frequent complication of BPA with an procedure is associated with improvements in car-
incidence as high as 53% to 60% as reported in some diopulmonary hemodynamics, pulmonary perfusion,
older studies (86,87). Several factors associated with exercise tolerance, World Health Organization func-
RPE following BPA include first procedure, severity of tional class, and 6-min walk distance (85,87–90,105).
baseline pulmonary hypertension, and a high level of Hemodynamic improvements, such as decrease in
plasma B-type natriuretic peptide (84,86). CTEPH mPAP and PVR, are proportional to the number of
patients with underdeveloped bronchial arteries are treated vessels (86–90). Pulmonary hypertension
more likely to develop RPE following the BPA pro- does not resolve immediately during or following a
cedure (101). Inami et al. (102), in a study of 150 BPA session, and it can take a few weeks to observe
consecutive BPA procedures in CTEPH, proposed the the positive impacts of the procedure (87–106).
Pulmonary Edema Predictive Scoring Index as a Studies have shown improvement in the quality of
product of PVR before BPA and the sum of changes in life and symptom resolution disproportionate to the
pulmonary flow grades with the procedure, to predict degree of reduction in pulmonary hypertension (107).
the risk of RPE following BPA. In their study, this Although the available data on long-term outcomes of
scoring index was the strongest factor among study BPA in CTEPH are limited (Table 5), persistence of
variables correlating with the occurrence of RPE (p < hemodynamic benefit (reduction in PVR and pulmo-
0.0001) and was a marker of the risk of RPE (cutoff nary artery pressure) of the BPA procedure at a me-
value 35.4, negative predictive value 92.3%). dian of 2.8 years after procedural completion (91) has
JACC VOL. 71, NO. 21, 2018 Mahmud et al. 2483
MAY 29, 2018:2468–86 Chronic Thromboembolic Pulmonary Hypertension
been observed. Recently, cumulative data from 7 showing the clinical feasibility of BPA for the treat-
centers in Japan for outcomes of over 308 inoperable ment of CTEPH. Riociguat remains the only approved
CTEPH patients treated with BPA (from 2004 to 2016; medical therapy and is an important adjunct for
1,408 procedures) was reported with 3-year survival treatment in patients deemed inoperable or with
of 94.5%, and a 44% reduction in mPAP (43.2 persistent pulmonary hypertension after PTE.
11.0 mm Hg to 24.3 6.4 mm Hg after final BPA) (93). In order for this disease to be appropriately
Complications including pulmonary injury (17.8%), treated, we recommend that expert CTEPH teams
hemoptysis (14.0%), and pulmonary artery perfora- including surgical specialists be developed at indi-
tion (2.9%) were not infrequent. vidual institutions. It is our opinion that BPA be
The initial experience at UC San Diego confirms the offered at CTEPH centers as a part of a multidisci-
efficacy and safety of the procedure. Using the tech- plinary approach to treatment decisions. Addition-
nique described in this paper, we have treated 38 ally, optimal and standardized techniques for BPA
patients (183 procedures) without any major compli- need to be developed along with dedicated inter-
cations (0%) but procedure-related minor hemoptysis ventional equipment and appropriate training stan-
of 6.6%. In the 20 patients who have completed 1-year dards. The majority of interventional outcomes data
follow-up, we have observed improvement in func- have been self-reported without adjudication, with
tional class, a 26% reduction in mPAP (39.1 heterogeneous techniques and paucity of long-term
8.9 mm Hg to 28.8 6.0 mm Hg) and 90% survival, outcomes. In order to adequately evaluate the suc-
with both deaths being unrelated to the BPA proced- cess of this procedure as compared with surgical
ure. Although difference in patient selection and endarterectomy, more rigorous and standardized
technique could be contributing to the differences in data collection are required. The cumulative benefit
outcomes between the various centers, it is clear that and adverse effect of multiple procedures, especially
the technique is effective with short-term efficacy on patient radiation exposure and renal contrast
and long-term durability. effects, must be determined. A multicenter evalua-
Improvement in right ventricular function has tion with objective adjudication for short-term suc-
been observed after BPA (103,108,109). Improved cess along with evaluation of long-term outcomes of
hemodynamics after BPA may lead to right ventricu- BPA are required before true equipoise can be
lar reverse remodeling, improved systolic function, established for randomized comparisons of BPA
and reduced subclinical myocardial injury with versus PTE for patients with segmental/sub-
reduced high-sensitivity troponin T level (110). Sec- segmental CTEPH. In the meantime, the percuta-
ondary positive effects of BPA on renal function have neous revascularization option is appropriate for
also been reported (111,112). A study of 9 CTEPH pa- patients deemed inoperable in combination with
tients with gradually deteriorated PVR at 4.1 (2.7 to targeted medical therapy, or those who have failed
7.9) years after PTE reported significant improvement to benefit from surgery. Whether BPA could poten-
in PVR of 4.2 (2.8 to 4.8) Wood units (p < 0.05) at 1.9 tially allow for discontinuation of targeted medical
(1.3 to 3.3) years after subsequent BPA procedure(s) therapy is unknown and should be carefully studied.
(92). Safety and efficacy of the procedure has also The ongoing RACE trial (Riociguat Versus Balloon
been demonstrated in elderly patients (age $65 years) Pulmonary Angioplasty in Non-operable Chronic
compared with younger patients, with similar change thromboEmbolic Pulmonary Hypertension;
of hemodynamics, rate of periprocedural complica- NCT02634203) is addressing the question of the
tions, length of intensive care unit and in-hospital comparative benefit of riociguat versus BPA for
stay, and all-cause mortality (113). inoperable CTEPH, and its results are eagerly
awaited.
CONTEMPORARY TREATMENT STRATEGIES
FOR CTEPH CONCLUSIONS
CTEPH is a disease that is underdiagnosed, and sur- There have been remarkable improvements in treat-
gical PTE remains the preferred therapy. However, ment options for CTEPH patients over the past
determination of operability can be challenging, re- decade. PTE remains the only definitive and poten-
quires an expert team, and availability of surgical tially curative therapy. Recent advancements in sur-
expertise is limited. There is growing excitement for gical techniques and instruments now allow distal
the percutaneous treatment of inoperable CTEPH endarterectomy, making surgery the treatment of
with data from multiple centers around the world choice even in patients with segmental or distal
2484 Mahmud et al. JACC VOL. 71, NO. 21, 2018
disease. On the basis of positive randomized clinical Due to these uncertainties, and with the evolving
trial data, we also have targeted medical therapy to management approaches, CTEPH patients should be
fill an unmet need for those deemed inoperable. referred to an advanced center experienced in the
Furthermore, BPA with the introduction of new evaluation and care of this unique patient population.
techniques and technologies now offers an alterna- The optimal treatment for any CTEPH patient re-
tive interventional treatment to PTE for select CTEPH quires a comprehensive review by a multidisciplinary
patients not amenable to surgery. However, despite team capable of providing all current treatment
the recent advances with BPA, there is no standard modalities.
technique for global adoption, and patient selection
remains a significant challenge. We still lack adequate ADDRESS FOR CORRESPONDENCE: Dr. Ehtisham
prospective long-term data after BPA, which high- Mahmud, University of California San Diego, Sulpizio
lights the need for future registries and carefully Cardiovascular Center, 9434 Medical Center Drive, La
conducted studies to determine the safety, efficacy, Jolla, California 92037. E-mail: emahmud@ucsd.edu.
and durability of the procedure. Twitter: @UCSDHealth.
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KEY WORDS balloon pulmonary
therapies; pulmonary endarterectomy and percu- monary edema predictive scoring index (PEPSI), a
angioplasty, BPA, chronic thromboembolic
taneous transluminal pulmonary angioplasty. PLoS new index to predict risk of reperfusion pulmonary
pulmonary hypertension, CTEPH, PTE,
One 2014;9:e94587. edema and improvement of hemodynamics in
pulmonary thromboendarterectomy
percutaneous transluminal pulmonary angio-
90. Taniguchi Y, Miyagawa K, Nakayama K, et al.
plasty. J Am Coll Cardiol Intv 2013;6:725–36.
Balloon pulmonary angioplasty: an additional
treatment option to improve the prognosis of 103. Fukui S, Ogo T, Morita Y, et al. Right ven- AP PE NDIX For a supplemental video and
patients with chronic thromboembolic pulmonary tricular reverse remodeling after balloon pulmo- its legend, please see the online version of this
hypertension. EuroIntervention 2014;10:518–25. nary angioplasty. Eur Respir J 2014;43:1394–402. paper.