After the Dawn ― Balloon Pulmonary Angioplasty for Patients With Chronic Thromboembolic Pulmonary Hypertension ―
論文ID: CJ-18-0258
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論文ID: CJ-18-0258
In the past 5 years, balloon pulmonary angioplasty (BPA) for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are deemed inoperable has undergone significant refinement. As a result, the procedure is now used worldwide and has become a promising therapeutic option for those patients. However, pulmonary endarterectomy remains the gold standard treatment for patients with CTEPH because the techniques and strategies for BPA are not yet unified. The best therapeutic option for each patient should be determined based on discussion among a multidisciplinary team of experts. For BPA to become an established treatment for CTEPH, further data are needed. This review summarizes the techniques and strategies of BPA at present and discusses the future development of the procedure.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease of obstructive pulmonary artery remodeling as a consequence of major vessel thromboembolism. The reported cumulative incidence of CTEPH is 0.1–9.1% within the first 2 years after a symptomatic event of pulmonary embolism.1,2 Pulmonary endarterectomy (PEA) is the gold standard therapy for CTEPH,1,3,4 and recently reported outcomes of PEA performed at expert centers have been excellent.4–6 However, the surgical technique of PEA requires proficiency and thus the procedure is performed at limited numbers of institutions.4–8 Patients deemed suitable for PEA are those in WHO functional class III or IV and with lesions mainly located in the lobar and segmental pulmonary arteries. Patients with lesions in the distal arteries and/or elderly patients and those with comorbidities have been considered to have an unfavorable risk/benefit ratio and are often deemed inoperable. Until recently these patients have had no effective treatment option and have had poor outcomes.9,10
Riociguat, a stimulator of soluble guanylate cyclase, is the only drug currently approved for inoperable CTEPH. In the CHEST-1 trial, riociguat was shown to significantly improve patients’ exercise capacity, pulmonary vascular resistance (PVR), and NT-proBNP levels.11 In a 1-year open-label extension trial (CHEST-2), patients maintained their improved exercise capacity and had an estimated 1-year survival of 97%.12 The most recent randomized controlled trial involving inoperable CTEPH patients was the MERIT-1 study, which investigated the efficacy of macitentan, an endothelin-receptor antagonist.13 In that trial, macitentan significantly improved the primary outcome of change in PVR from baseline to week 16, compared with placebo. Although it has not yet been approved for CTEPH patients, macitentan may have beneficial effects in this population, but its efficacy over the longer term has not been established.
Balloon pulmonary angioplasty (BPA) is an alternative therapy for inoperable patients with CTEPH.1 This interventional treatment uses a balloon catheter to dilate the pulmonary stenosis. Patients who undergo BPA show significant improvement in pulmonary hemodynamics as well as in electrocardiographic, chest X-ray, echocardiographic, and perfusion lung scan findings (Figure 1).
Representative case of chronic thromboembolic pulmonary hypertension (CTEPH) treated successfully with balloon pulmonary angioplasty (BPA). Findings from a 61-year-old woman with CTEPH (A) before BPA and (B) after 6 BPA procedures. ECG (Left panels in A and B) demonstrates improvement of right-axis deviation, complete right bundle branch block, and right ventricular hypertrophy after BPA. Chest radiography (Right upper panels) shows improvement of cardiomegaly after BPA. Echocardiography (Right middle panels) shows improvement in the deformity of the left ventricle after BPA. Lung perfusion scan (Right lower panels) shows improvement in perfusion defects, especially in the right upper and lower fields. Pulmonary arterial pressure decreased from 72/33 (47) to 31/11 (19) mmHg. Pulmonary vascular resistance decreased from 904 to 179 dyne·s·cm−5.
BPA has been performed for inoperable CTEPH cases since 1988.14–16 However, the treatment effects have been less favorable than those obtained with PEA and severe complications have been frequently observed. More than 20 years after the first report of BPA for CTEPH, the procedure is still not widely accepted as a therapeutic option for inoperable patients. We have tried to improve the efficacy and safety of BPA to help these patients, and in 2012 we reported our initial case series of BPA in 68 inoperable patients with CTEPH.17 Other Japanese institutions have also published BPA studies,18,19 and the procedure was covered at the Fifth World Symposium on Pulmonary Hypertension in 2013.3 The latest guidelines name BPA as a treatment option for patients who are ineligible for PEA1. BPA is now performed outside Japan as well, and the efficacy of the procedure has been confirmed in selected patients.20–23
The latest guidelines for the diagnosis and treatment of pulmonary hypertension (PH) recommend that assessment of operability and treatment decisions for all patients with CTEPH should be made by a multidisciplinary team of experts.1 Interventional BPA may be considered in patients who are technically inoperable or who have an unfavorable risk/benefit ratio for PEA (Class IIb/Evidence level C). Candidates for BPA are patients who are unsuitable for PEA, including those with surgically inaccessible lesions, those who are inoperable because of comorbidities, and those with residual or recurrent PH after PEA. Generally, patients with WHO functional class ≥III, mean pulmonary arterial pressure (PAP) ≥30 mmHg, or PVR ≥300 dyne·s·cm−5 are selected.24 Severity of hemodynamics and older age are not necessarily contraindications for BPA.17–19,25–27
Before BPA, pulmonary angiography (global or from both main pulmonary arteries) should be performed. It is essential to understand the distribution of the thromboembolic lesions seen with pulmonary angiography and lung perfusion scans and to plan which lesions to treat first. Most BPA procedures are currently approached through the right femoral vein.28 A 9Fr sheath is inserted into the vein, through which a 6Fr long introducer sheath is advanced into the pulmonary artery. After the sheaths are inserted, heparin is administered to reach an activated clotting time of approximately 200s. Subsequently, a 6Fr guiding catheter is advanced into the pulmonary artery being treated (Figure 2A). During the treatment procedures, we perform selective pulmonary angiography to evaluate lesion characteristics precisely; we choose our strategy according to lesion distribution and characteristics. After deciding which lesion to treat, a 0.014-inch guidewire is used to cross the lesion (Figure 2B). Then, a balloon catheter of an appropriate diameter (1.5–10 mm) is selected to dilate the lesion (Figure 2C). We currently use small balloons (≤2.0 mm) at the initial treatment and stenotic lesions remain after the initial ballooning (Figure 2D). Although angiographic evidence of stenosis remains immediately after BPA, vessel diameter spontaneously expands over time (Figure 2E), as we previously reported in a case of spontaneous enlargement of the pulmonary artery after successful BPA.29 Later, we perform a final balloon dilatation with appropriately sized balloons, according to the proximal reference diameter (Figure 2F,G).
Balloon pulmonary angioplasty (BPA) procedure. (A) Web lesion is noted on selective pulmonary angiography through a 6Fr guiding catheter before BPA. (B) After passage of a 0.014-inch guidewire, pulmonary angiography shows increased blood flow to the peripheral arteries. (C) Balloon (3.0 mm) is inflated at the lesion. (D) Stenosis remains after the initial ballooning, with increased flow to the peripheral arteries compared with Figure 2A. (E) Without further ballooning, vessel diameter has spontaneously expanded after 1 week. (F) Final balloon dilatation is performed with a larger balloon (4.0 mm) at the same lesion. (G) Selective pulmonary angiography after final ballooning shows improvement of stenosis and increased flow in the peripheral arteries.
We previously used a balloon size that matched the size of the pulmonary artery at the initial BPA procedure. Patients treated with that method sometimes experienced severe pulmonary hemorrhage after treatment. In pathologically examined lesions after BPA, we found a small incision through the organized thrombus in 1 case,30 and dissection of the tunica media with partial detachment of the organized thrombus from the vascular wall in other cases (Figure 3).31 Thus, the thrombi were not extracted from inside the blood vessel as in PEA, but were forced to one side to enlarge the lumen.
Schematic diagram of proposed mechanism of balloon pulmonary angioplasty (BPA) dilating pulmonary occlusive lesions. (Cited from Kitani M, et al.31) Structure of a pulmonary artery with organized thrombus (green) and recanalized channels (red) (Left) is thought to be changed by BPA (Right). The lumen is opened wide by dissection in the medial wall and the organized thrombus is compressed to one side. Newly formed intima (blue) covers the inner surface of the dissected pulmonary artery.
We chronologically measured perfusion pressure in the pulmonary artery before and after BPA (Figure 4). We observed an increase in the PAP distal to the obstruction immediately after BPA, although angiography revealed persistent stenosis. Vessel diameter spontaneously expanded over time and ultimately the pressure gradient across the lesion was eliminated. Given our previous observation of vessel wall dissection caused by BPA,31 we speculate that pressure overload in the pulmonary artery with partial detachment of an organized thrombus may cause dilatation of the artery distal to the occlusion. For this reason, we recently began to use small balloons at the initial dilatation, increasing the diameter of dilatation at subsequent procedures, a protocol that increases safety by avoiding vascular complications. To determine when to stop dilatation, some institutions use the fractional flow reserve;32 however, this approach may increase the risk of vascular injury because the fractional flow reserve of the pulmonary arteries is usually very low (Figure 4).
Selective pulmonary angiography images and pulmonary artery pressure recordings proximal and distal to the lesion before (A), immediately after (B), and 2 months after (C) balloon pulmonary angioplasty (BPA). (A) Selective pulmonary angiography image before BPA (Upper panel). Severe stenosis (arrow) is seen in left A9 and the vessel distal to the lesion is not visualized. Pressure recordings before BPA (Lower panel). Proximal systolic pulmonary artery pressure is >50 mmHg. The pressure recording distal to the lesion was ≈10 mmHg and is similar to the pulmonary artery wedge pressure recording. (B) Selective pulmonary angiogram immediately after BPA (Upper panel). Residual stenosis (arrow) is recognized; however, blood flow distal to the lesion has improved. Pressure waveform immediately following BPA (Lower panel). Proximal pulmonary artery pressure is similar to that seen in (A). Distal pulmonary artery pressure has increased and shows a similar waveform to that of pulmonary artery pressure. (C) Selective pulmonary angiogram 2 months after BPA (Upper panel). Stenosis (arrow) has improved despite no additional ballooning being performed. Blood flow within the vessel distal to the lesion has improved compared with immediately after the procedure. Pressure waveform 2 months after BPA (Lower panel). Proximal pulmonary artery pressure has decreased after additional BPA procedures in other lesions. Distal pulmonary artery pressure remains increased, with decreased pressure gradient between proximal and distal pulmonary arterial pressures.
Patients with CTEPH may have lesions in all 18 segmental pulmonary arteries. In our initial series report of BPA, we demonstrated that dilatation of a greater number of segments was associated with a greater decrease in mean PAP.17 Treatment of only 1 or 2 segments per procedure is not sufficient. To achieve a sufficient reduction in PAP, we need to treat as many arteries as possible in a limited time and with as little radiation as possible.
Currently, we dilate as many lesions as possible in a single procedure; however, the maximum duration of radiographic fluoroscopy in a single procedure is limited to 60 min. Therefore, lesions at 14–16 sites are generally treated in a single procedure. To enhance the therapeutic effect of BPA, it is important to create a large reperfusion area, which requires repeated treatments, with 3 or 4 procedures per patient (Table). To make it possible, operators must be highly skilled at engaging catheters and wires precisely and quickly and holding them tightly during the procedure.
| BPA operator level | ||
|---|---|---|
| Beginner-average | Experienced | |
| Total number of procedures/patient | 5–6 | 3–4 |
| Radiation time/procedure | 50 min | 30 min |
| Amount of contrast medium/procedure | 150–200 mL | 80–100 mL |
| Segments/procedure | 2–4 | 8–10 |
| Lesions/procedure | 2–4 | 14–16 |
| Mean PAP after BPA | <30 mmHg | <25 mmHg |
| Oxygen saturation in room air after BPA | >90% | ≥95% |
BPA, balloon pulmonary angioplasty; PAP, pulmonary arterial pressure.
The most frequent complication of BPA is hemosputum or hemoptysis resulting from lung injury. This was initially considered to be the same as reperfusion pulmonary edema,15 which is a major postoperative complication of PEA. Now it is thought that most pulmonary hemorrhage in BPA results from mechanical injury caused by perforation of the pulmonary artery by the wire or by balloon over-dilatation.22,28 Because mechanical ventilation and percutaneous cardiopulmonary support are required in severe cases, it is important to minimize the occurrence of these complications and to implement appropriate measures (balloon inflation, coil embolization, or covered stents33–35) in the event of lung injury. The reported complication rate varies among reports from ∼1.0% to 52.9% of procedures, with approximately 30% in many reports.15,17–19,21,22,36–42
Simply avoiding vascular injury reduces the risk of lung injury. It is essential to keep the tip of the guidewire within the angiographically visible range of the distal vessels. In addition, it is important to avoid over-dilatation of the lesions. In BPA, lumen diameter widens as the thrombus is forced to one side.31 For this reason, there is a risk that over-dilatation of pulmonary arteries will lead to vascular injury. We modified the previous angiographic classification to establish the following new classification of lesions, which is suitable for BPA: type A, ring-like stenosis lesion; B, web lesion; C, subtotal lesion; D, total occlusion lesion; and E, tortuous lesion (Figure 5).38 A review of pulmonary angiography images and CT images after BPA indicates that the complication rate and success rate vary among lesion types. The success rate was higher and the complication rate was lower for ring-like stenosis and web lesions. Total occlusion lesions had the lowest success rate and the complication rate was higher for subtotal lesions.38 Thus, we need to choose an appropriate balloon size according to the type of lesion. Smaller sized balloons are better for lesions with higher complication rates.
Angiographic classification of lesion morphology based on lesion opacity and the blood flow distal to the lesion. (Cited from Kawakami T, et al.38) (A) Ring-like stenosis lesion. (B) Web lesion. (C) Subtotal lesion. (D) Total occlusion lesion. (E) Tortuous lesion. Types A–D are located proximal to the subsegmental pulmonary artery, namely, the segmental and subsegmental arteries. Type E lesions are located distal to the subsegmental artery.
In a multicenter registry, complications occurred in 36.3% of BPA procedures, including pulmonary injury (17.8%), hemoptysis (14.0%), and pulmonary artery perforation (2.9%).42 Although the complication rate in that study was not low, only 5.5% of patients required mechanical ventilation. A total of 8 patients (2.6%) died within 30 days after BPA and 4 more patients died during follow-up. The in-hospital death rate in the first report of BPA was 5.6%;15 the rate was mostly lower in subsequent reports, with some exceptions of 10%.22
Most reports on BPA that include more than 10 patients have demonstrated that pulmonary hemodynamics normalize with a mean PAP reduction of 10–20 mmHg from baseline after 4 or 5 procedures.15,17–19,21,22,26,36–45 We recently reported the results of 500 BPA procedures (1,936 treated lesions) in 97 CTEPH patients, the largest series from a single center.38 The average number of BPA procedures per patient was 5.2±3.1 (median, 5). Mean PAP significantly decreased from 45.1±10.8 to 23.3±6.4 mmHg; PVR decreased from 960.6±457.8 to 314.5±150.4 dyne·s·cm−5. We succeeded in decreasing mean PAP by >20 mmHg to an absolute pressure of <25 mmHg.
In the only multicenter retrospective study of BPA, a total of 308 patients (62 men, 246 women; mean age, 61 years) underwent 1,408 procedures at 7 institutions in Japan.42 During the study period, a median of 4 procedures were performed per person (range, 1–24 procedures/person). Hemodynamics significantly improved in 249 patients (1,154 procedures). In 196 patients who underwent follow-up right heart catheterization, the improvement in hemodynamic parameters was maintained. Mean PAP decreased from 43.2±11.0 to 24.3±6.4 mmHg after final BPA and to 22.5±5.4 mmHg at follow-up, with a significant reduction in concomitant use of PH-targeted therapy and oxygen supplementation (Figure 6).42 Overall survival after the final BPA procedure was 98.9% at 1, 2, and 3 years, which was comparable to survival after PEA. Other single center-based reports with smaller numbers of patients reported favorable mid-term efficacy, with improved hemodynamics and exercise capacity after BPA.41,46
Balloon pulmonary angioplasty (BPA) results from a multicenter registry. (Cited from Ogawa A, et al.42) Parameters before BPA (n=308), immediately after final BPA (n=249), and at follow-up (n=196) were compared. World Health Organization functional class (WHO FC; A), mean pulmonary arterial pressure (mPAP; B), cardiac index (CI; C), and pulmonary vascular resistance (PVR; D) were significantly improved immediately after final BPA, and the improvement was maintained at follow-up.
The rapid spread of BPA worldwide has resulted in improved understanding of CTEPH itself. Over the past decades, cardiologists have focused on treating systemic arteries with interventional techniques. In treating CTEPH, we have been surprised at the differences between systemic and pulmonary arteries, including pathological characteristics, such as the cells and space-occupying materials. Furthermore, intervention in systemic arteries is relatively easier because the vessels have firm vascular walls and are surrounded by firm tissues such as muscles. Because pulmonary arteries are surrounded by fragile alveoli, not all techniques of arterial intervention can be applied to BPA. There seems to be no need to implant stents in pulmonary arteries and major/severe complications of BPA differ from those of interventions in systemic arteries.
Information from several single center-based BPA studies in Japan indicates that patient characteristics are quite different between Japanese and Western countries. Japanese patients who have undergone BPA are predominantly female (∼80%) and are older than Western patients (in their 60 s),42 although there is no sex bias regarding operability in Japan. A previous Japanese cohort study on CTEPH also found a female predominance.47 Furthermore, Japanese patients have fewer of the risk factors reported to be associated with CTEPH in previous studies from outside Asia. These curious discrepancies may be related to ethnicity48 or to differences in proximal vs. distal disease.
With the widespread use of BPA, we now realize there are more patients with CTEPH than we initially thought. Is the incidence of CTEPH truly increasing? We usually say that “CTEPH is considered a rare complication of acute pulmonary embolism”. However, we know that only 4% of patients develop CTEPH after acute pulmonary embolism and that many patients with CTEPH have never had an episode of acute pulmonary embolism.49 What is the cause of CTEPH?
There has been a huge evolution in BPA strategy and technique in the past 5 years since the initial report of BPA refinement in 2012. However, a lack of consensus persists regarding various procedural factors. When should BPA procedures be terminated in each patient? Which imaging modality is best for identifying target lesions? What exactly is BPA-related lung injury? Should PH-targeted drugs be started before BPA? Which patients benefit most from the procedure? Who is not suitable for BPA? What is the most efficient approach to maximize the results of BPA?
For some of these questions, we have our own interim answers. The target of BPA treatment should be the same as that of PEA: achievement of a mean PAP <25 mmHg without PH-targeted drugs and ultimately improvement in patient prognosis. Regarding the best imaging modality for selecting target lesions, we routinely use only selective pulmonary angiography (Figure 2). Because most other imaging modalities that are reported to be useful in selecting target lesions are performed before patients enter the catheter room, they may not be very useful when performing BPA. CTEPH lesions are present in all pulmonary arteries and we need to treat as many lesions as possible to achieve sufficient improvement in mean PAP. We ultimately need to dilate all reachable lesions; to accomplish this goal we do not need a beautiful image, but we do need an imaging technique that facilitates passage of the wire to all lesions. Furthermore, after we treat proximal lesions, we can visualize whether there are distal lesions or not, which is unclear before ballooning. Only selective pulmonary angiography performed during the BPA procedure allows accurate and precise visualization of these lesions. We can then evaluate distal lesion characteristics and develop an ad hoc strategy if necessary.
There is increasing circumstantial evidence that BPA-related lung injury is mainly caused by vascular complications. However, more data are needed to confirm this suspicion. What is the mechanism of lumen enlargement? Do vascular lesions ever recur after successful BPA, although there has been no report of recurrence, unlike in systemic arteries, after simple ballooning without stenting? Do any lesions need stenting? Although patients need life-long anticoagulation, the efficacy of direct oral anticoagulants in CTEPH patients after BPA has not been clarified. A previous study demonstrated that various PH-targeted drugs (which are off-label for CTEPH patients) do not effectively lower the mean PAP in patients with CTEPH who need PEA.50 The CHEST-1 trial found a reduction in mean PAP of only 5 mmHg.11 Most reports on BPA have demonstrated improvement in mean PAP by >10 mmHg.22 All PH drugs tested as treatment options for CTEPH failed to improve mean PAP by this much. Successful BPA can benefit patients more than PH-targeted drugs, although there is no trial to directly compare BPA and PH-targeted drugs. After successful BPA, there seems to be no benefit to using off-label PH-targeted drugs in this patient population, though direct evidence is still lacking.
Many questions remain to be answered in the near future. Should patients with chronic thromboembolic disease (without PH) undergo BPA?51 We probably need to think about the criteria for performing BPA in this population and how to evaluate the efficacy of treatment, because these patients are not currently candidates for PEA or PH-targeted drugs. Because the indications for BPA vary among institutions at present, we should limit the use of BPA to patients with PH. Many studies have concluded that right ventricular function improves after BPA. However, many of these results simply show the consequence of decreasing afterload. To prove actual improvement of right ventricular function, we need to confirm improvement in end-systolic elastance or ventriculo-arterial coupling.52,53
Now that BPA is listed as Class IIb/Evidence level C in the latest guidelines,1 we need to more firmly establish BPA as a treatment option for patients with CTEPH. However, there is a huge variation in methods and strategies of BPA, as well as in the skill and techniques of operators; consensus is needed on the fundamental issues. To enable the development of consensus, we need to gather patients at CTEPH referral centers and discuss the operability and suitability of BPA in a multidisciplinary team. We still need to accumulate experience and hone our skills to offer the best practice of BPA. We need to expand the treatment area with less radiation time and less contrast medium.
Is there any possibility of hybrid therapy with PEA and BPA?54–56 If so, which procedure should be performed first? How long after the first procedure should the second be performed? Some expert operators caution that the plane for PEA is damaged by BPA and that BPA should never be performed before PEA. The need for randomized controlled trials to evaluate the comparative advantages of BPA and PEA has recently been discussed. Such trials might be unrealistic to pursue at this moment because of the huge variation in BPA methods at different institutions and the variability in the skills of operators in performing both BPA and PEA. This discussion, however, suggests that although refined BPA began as an option only for patients who were technically ineligible for PEA and for those with an unfavorable risk/benefit ratio with PEA, people now recognize that the indications for BPA and PEA overlap, depending on the situation, including the availability of skilled operators in each country and patients’ characteristics.
BPA has become a solution for patients with CTEPH who are ineligible for PEA and who have no other effective therapeutic option. BPA has broadened our horizons and we have come to realize that there is more to learn regarding CTEPH and BPA. After the dawn of refinement of BPA to treat CTEPH, the need for further development remains.
A.O. has no conflicts of interest. H.M. received lecture fees from Actelion Pharmaceuticals Japan, Ltd., AOP Orphan Pharmaceuticals AG, Bayer Yakuhin, Ltd., Nippon Shinyaku, Co., Ltd., Pfizer Japan, Inc., and Kaneka Medix Corporation.
