Michael J. Landzberg

Bosentan Therapy in Patients With Eisenmenger Syndrome A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study

Background— Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease. Because Eisenmenger syndrome is associated with increased endothelin expression, patients may benefit from endothelin receptor antagonism. Theoretically, interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia. Methods and Results— The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) was a 16-week, multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of bosentan, a dual endothelin receptor antagonist, on systemic pulse oximetry (primary safety end point) and pulmonary vascular resistance (primary efficacy end point) in patients with World Health Organization functional class III Eisenmenger syndrome. Hemodynamics were assessed by right- and left-heart catheterization. Secondary end points included exercise capacity assessed by 6-minute walk distance, additional hemodynamic parameters, functional capacity, and safety. Fifty-four patients were randomized 2:1 to bosentan (n=37) or placebo (n=17) for 16 weeks. The placebo-corrected effect on systemic pulse oximetry was 1.0% (95% confidence interval, −0.7 to 2.8), demonstrating that bosentan did not worsen oxygen saturation. Compared with placebo, bosentan reduced pulmonary vascular resistance index (−472.0 dyne · s · cm−5; P=0.0383). The mean pulmonary arterial pressure decreased (−5.5 mm Hg; P=0.0363), and the exercise capacity increased (53.1 m; P=0.0079). Four patients discontinued as a result of adverse events, 2 (5%) in the bosentan group and 2 (12%) in the placebo group. Conclusions— In this first placebo-controlled trial in patients with Eisenmenger syndrome, bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation.

Closure or Medical Therapy for Cryptogenic Stroke with Patent Foramen Ovale

BACKGROUND The prevalence of patent foramen ovale among patients with cryptogenic stroke is higher than that in the general population. Closure with a percutaneous device is often recommended in such patients, but it is not known whether this intervention reduces the risk of recurrent stroke. METHODS We conducted a multicenter, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had a patent foramen ovale. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years. RESULTS A total of 909 patients were enrolled in the trial. The cumulative incidence (Kaplan-Meier estimate) of the primary end point was 5.5% in the closure group (447 patients) as compared with 6.8% in the medical-therapy group (462 patients) (adjusted hazard ratio, 0.78; 95% confidence interval, 0.45 to 1.35; P=0.37). The respective rates were 2.9% and 3.1% for stroke (P=0.79) and 3.1% and 4.1% for TIA (P=0.44). No deaths occurred by 30 days in either group, and there were no deaths from neurologic causes during the 2-year follow-up period. A cause other than paradoxical embolism was usually apparent in patients with recurrent neurologic events. CONCLUSIONS In patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA. (Funded by NMT Medical; ClinicalTrials.gov number, NCT00201461.).

Long-Term Survival, Modes of Death, and Predictors of Mortality in Patients With Fontan Surgery

Background— To better define determinants of mortality in patients with univentricular physiology, a database registry was created of patients born in 1985 or earlier with Fontan surgery who were followed up at Children’s Hospital Boston. Methods and Results— A total of 261 patients, 121 of whom (46.4%) were women, had a first Fontan surgery at a median age of 7.9 years: right atrium–to–pulmonary artery connection in 135 (51.7%); right atrium to right ventricle in 25 (9.6%); and total cavopulmonary connection in 101 (38.7%). Over a median of 12.2 years, 76 (29.1%) died, 5 (1.9%) had cardiac transplantation, 5 (1.9%) had Fontan revision, and 21 (8.0%) had Fontan conversion. Perioperative mortality decreased steadily over time and accounted for 68.4% of all deaths. In early survivors, actuarial freedom from death or transplantation was 93.7%, 89.9%, 87.3%, and 82.6% at 5, 10, 15, and 20 years, respectively, with no significant difference between right atrium to pulmonary artery versus total cavopulmonary connection. Late deaths were classified as sudden in 7 patients (9.2%), thromboembolic in 6 (7.9%), heart failure–related in 5 (6.7%), sepsis in 2 (2.6%), and other in 4 (5.2%). Most sudden deaths were of presumed arrhythmic origin with no identifiable predictor. Independent risk factors for thromboembolic death were lack of antiplatelet or anticoagulant therapy (hazard ratio [HR], 91.6; P=0.0041) and clinically diagnosed intracardiac thrombus (HR, 22.7; P=0.0002). Independent predictors of heart failure death were protein-losing enteropathy (HR, 7.1; P=0.0043), single morphologically right ventricle (HR, 10.5; P=0.0429), and higher right atrial pressure (HR, 1.3 per 1 mm Hg; P=0.0016). Conclusion— In perioperative survivors of Fontan surgery, gradual attrition occurs predominantly from thromboembolic, heart failure–related, and sudden deaths.

Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review.

Despite extensive evaluation, the cause of ischemic stroke remains undefined in approximately 40% of patients (1-4). Passage of thromboemboli from the right to left atrium across a patent foramen ovale, a remnant of the fetal circulation, has been postulated as a mechanism responsible for some of these cryptogenic strokes. Thrombus straddling a patent foramen ovale has been imaged on rare occasions (5-8). The association between patent foramen ovale and cryptogenic embolic stroke has been strengthened by epidemiologic studies that found a prevalence of patent foramen ovale of 44% to 66% in patients with cryptogenic stroke compared with 27% in autopsy series of all-cause death (2, 9-13). The most appropriate therapy to prevent recurrent events in survivors of cryptogenic stroke or transient ischemic attack with documented patent foramen ovale is unknown and controversial. Traditionally, a conservative strategy of long-term medical therapy with antiplatelet agents or oral anticoagulants has been used. However, much debate exists over which agent provides the most favorable riskbenefit ratio. Surgical closure of patent foramen ovale has been proposed, but outcomes have varied (14-16). In the past decade, closure by implantation of a transcatheter device has emerged as a feasible low-risk alternative therapeutic option, but comparative studies are lacking. We therefore performed a systematic review to synthesize the current state of knowledge on transcatheter closure of patent foramen ovale compared with medical therapy. Methods Literature Search and Study Selection Relevant articles published between January 1985 through July 2003 were identified through an electronic search of the MEDLINE database by using the following query terms: patent foramen ovale or persistent foramen ovale combined with stroke, embolism, embolus, embolization, cerebral, cerebrovascular, and closure. This strategy was supplemented by a manual search of secondary sources, including selected references from primary articles. Both English-language and foreign-language journals were examined. Unpublished data were not sought. In the absence of controlled trials, identified articles were systematically screened for the following inclusion criteria: a study cohort that had secondary prevention of neurologic thromboembolic events by medical management of patent foramen ovale or transcatheter device implantation; minimum of 10 patients per cohort; assessment and report of neurologic thromboembolic events; mean duration of follow-up of at least 12 months (because the primary outcome of interest was the 1-year rate of recurrent events); and actuarial freedom from recurrent neurologic thromboembolic events at 1 year, as recorded or calculated from sufficient data. When more than 1 article originating from the same center met the above criteria, the study that reported on the most patients was included and those with fewer patients were excluded to avoid duplication. Data Synthesis Study Identification We identified 236 articles, of which 20 met the prespecified inclusion criteria (Figure 1). Four studies with potentially overlapping samples were excluded. Thus, 16 articles including 2250 patients were reviewed: 10 studies (1355 patients) on transcatheter closure and 6 studies (895 patients) on medical management. Table 1 shows the details of individual studies. Figure 1. Study identification. Table 1. Baseline Characteristics Definitions All patients were treated for presumed paradoxical emboli associated with patent foramen ovale. When defined, patent foramen ovale was described as spontaneous or provocable right-to-left interatrial shunting on contrast echocardiography. The maximum number of cardiac cycles allowed after right atrial opacification when assessing contrast in the left atrium was 3 (17-20) or 5 (21). The threshold for the number of left atrial microbubbles that were considered significant was 1 (17, 20, 22, 23), 3 (18, 19, 24, 25), or 4 (21). The most common definition of an aneurysmal or hypermobile atrial septum was septal movement into the right or left atrium exceeding 10 mm (20, 22, 23, 25-27). Other definitions included membrane mobility of 6.5 mm or greater (18), 11 mm (19), or 15 mm (21, 28) or diameter of the mobile portion of septum primum greater than 13 mm (27) or 15 mm (21). The outcomes and means of their assessment were not uniform among studies. When defined, transient ischemic attack was characterized as a transient reversible neurologic defect confirmed by a neurologist that resolved completely within 12 hours (25) or 24 hours (18, 22-24, 28, 29). Stroke was defined as a clinically and neuroradiologically confirmed focal deficit persisting for more than 24 hours (18-20, 22-25, 28, 29). Rigor of follow-up and surveillance for end points differed among the reports and was often liberally described as standard neurologic care. Patient Characteristics Among patients undergoing transcatheter closure of patent foramen ovale, the mean age per study ranged from 40 12 years to 50 12 years. In contrast, medically treated patients had a mean age older than 50 years in 3 of 6 studies. Overall, one third to two thirds of patients in studies of transcatheter device closure were male, whereas all studies of medically managed patients that reported sex included more men than women. A tendency toward a higher prevalence of risk factors for atherosclerosis was noted in medically managed patients. In studies of transcatheter device closure that reported such risk factors, hypertension was documented in 10% to 28% of patients, diabetes in 0% to 7%, and smoking in 14% to 36%. In contrast, medically managed patients had prevalences of hypertension, diabetes, and smoking of 9% to 53%, 3% to 84%, and 31% to 85%, respectively. No major differences were noted in the prevalence of hypercholesterolemia among patients having transcatheter closure (11% to 26%) and those receiving medical therapy (12% to 30%). Data were insufficient to analyze body mass index or the prevalence of previous recognized symptomatic atherosclerotic heart or peripheral vascular disease. Atrial septal aneurysms were present in a similar proportion of patients undergoing transcatheter closure (15% to 34%) or medical therapy (12% to 37%). The type of cerebrovascular accident, classified as stroke or transient ischemic attack, varied among patients who had transcatheter closure. However, all studies of medically treated patients that subclassified type of cerebrovascular accident reported a prevalence of previous stroke of at least 50% (100% of patients in the 2 largest studies). Multiple cerebrovascular events were, however, more common in patients undergoing transcatheter closure (10% to 75%, compared with 2% to 28% in 3 studies of medically treated patients that reported this information). Medical Therapy Medical treatment varied among the patients in this review. Antiplatelet therapy consisted of a daily prescribed aspirin dosage of 250 mg (21), 300 mg (19), or 325 mg (17, 20) or a mean (SD) dose of 233 83 mg (23). A minority of patients received clopidogrel or ticlopidine (17, 23). In anticoagulated patients, target international normalized ratios were 1.4 to 2.8 (20), 2.0 to 3.0 (23), 3.0 to 4.0 (21), or undefined (17, 18). Although therapy was randomly allocated in 1 study (20), in most patients, medical management decisions were individualized according to the discretion of the treating physician. Adherence to therapy was assessed monthly (20) or at 6-month intervals (19), or was not stated (17, 18, 21, 23). Transcatheter Device Closure Table 2 shows reported complications of closure of patent foramen ovale by using a transcatheter device. Technical procedural success, imaging techniques to assess complete closure, and device-related complications were not uniformly defined. Individual characteristics of patients who had complete closure after device implantation were not recorded, thereby limiting analysis. Table 2. Complications of Transcatheter Closure of Patent Foramen Ovale Major complications were death (26), hemorrhage requiring blood transfusion (27), cardiac tamponade (22, 24, 27, 28), need for surgical intervention (30), and massive fatal pulmonary emboli (24, 25, 27, 28, 31). Minor complications were defined differently in each study and included bleeding not requiring transfusion (27), periprocedural atrial arrhythmias (24-26, 30), transient atrioventricular node block (25), device arm fractures (25, 31), device embolization with successful catheter retrieval (22, 25-27), asymptomatic device thrombosis (25, 26), need for recatheterization (22, 26), symptomatic air embolism (22, 25, 28), transient ST-segment elevation (25, 27), arteriovenous fistula formation (22), and femoral hematoma (28). According to this classification scheme, the reported incidence of major and minor complications was 1.5% and 7.9%, respectively. Antiplatelet or anticoagulant regimens after transcatheter closure of patent foramen ovale differed in the clarity of definition, duration of therapy, and assessment of compliance. Regimens consisted of daily aspirin, 3 to 5 mg/kg of body weight (27), 5 to 10 mg/kg (29, 30), 81 mg (32), 100 mg (22, 25), or 325 mg (24), with or without clopidogrel, 75 mg/d (24-26), or ticlopidine, 250 mg twice daily (24). Aspirin therapy was continued for 6 to 12 weeks (30), 6 months (22, 26-29, 31), or 12 months (25). Most patients receiving warfarin did so for indications other than transcatheter closure of patent foramen ovale. Recurrence of Neurologic Thromboembolic Events Although the mean ( SD) duration of follow-up was similar in studies of transcatheter device closure (12 6 months to 47 14 months) and studies of medical management (13 11 to 43 27 months), pattern analysis suggests an overall longer duration of follow-up in medically managed patients (Table 3). The mean duration of follow-up was 1 or 2 years in 6 of 10 studies of transcatheter device

Pregnancy Outcomes in Women With Congenital Heart Disease

Background— Pregnant women with congenital heart disease are at increased risk for cardiac and neonatal complications, yet risk factors for adverse outcomes are not fully defined. Methods and Results— Between January 1998 and September 2004, 90 pregnancies at age 27.7±6.1 years were followed in 53 women with congenital heart disease. Spontaneous abortions occurred in 11 pregnancies at 10.8±3.7 weeks, and 7 underwent elective pregnancy termination. There were no maternal deaths. Primary maternal cardiac events complicated 19.4% of ongoing pregnancies, with pulmonary edema in 16.7% and sustained arrhythmias in 2.8%. Univariate risk factors included prior history of heart failure (odds ratio [OR], 15.5), NYHA functional class ≥2 (OR, 5.4), and decreased subpulmonary ventricular ejection fraction (OR, 7.7). Independent predictors were decreased subpulmonary ventricular ejection fraction and/or severe pulmonary regurgitation (OR, 9.0) and smoking history (OR, 27.2). Adverse neonatal outcomes occurred in 27.8% of ongoing pregnancies and included preterm delivery (20.8%), small for gestational age (8.3%), respiratory distress syndrome (8.3%), intraventricular hemorrhage (1.4%), intrauterine fetal demise (2.8%), and neonatal death (1.4%). A subaortic ventricular outflow tract gradient >30 mm Hg independently predicted an adverse neonatal outcome (OR, 7.5). Cardiac risk assessment was improved by including decreased subpulmonary ventricular systolic function and/or severe pulmonary regurgitation (OR, 10.3) in a previously proposed risk index developed in pregnant women with acquired and congenital heart disease. Conclusions— Maternal cardiac and neonatal complication rates are considerable in pregnant women with congenital heart disease. Patients with impaired subpulmonary ventricular systolic function and/or severe pulmonary regurgitation are at increased risk for adverse cardiac outcomes.

Ventricular size and function assessed by cardiac MRI predict major adverse clinical outcomes late after tetralogy of Fallot repair

Background: Factors associated with impaired clinical status in a cross-sectional study of patients with repaired tetralogy of Fallot (TOF) have been reported previously. Objectives: To determine independent predictors of major adverse clinical outcomes late after TOF repair in the same cohort during follow-up evaluated by cardiac magnetic resonance (CMR). Methods: Clinical status at latest follow-up was ascertained in 88 patients (median time from TOF repair to baseline evaluation 20.7 years; median follow-up from baseline evaluation to most recent follow-up 4.2 years). Major adverse outcomes included (a) death; (b) sustained ventricular tachycardia; and (c) increase in NYHA class to grade III or IV. Results: 22 major adverse outcomes occurred in 18 patients (20.5%): death in 4, sustained ventricular tachycardia in 8, and increase in NYHA class in 10. Multivariate analysis identified right ventricular (RV) end-diastolic volume Z ⩾7 (odds ratio (OR) = 4.55, 95% confidence interval (CI) 1.10 to 18.8, p = 0.037) and left ventricular (LV) ejection fraction <55% (OR = 8.05, 95% CI 2.14 to 30.2, p = 0.002) as independent predictors of outcome with an area under the receiver operator characteristic curve of 0.850. LV ejection fraction could be replaced by RV ejection fraction <45% in the multivariate model. QRS duration ⩾180 ms also predicted major adverse events but correlated with RV size. Conclusions: In this cohort, severe RV dilatation and either LV or RV dysfunction assessed by CMR predicted major adverse clinical events. This information may guide risk stratification and therapeutic interventions.

Implantable Cardioverter-Defibrillators in Tetralogy of Fallot

Background— Tetralogy of Fallot is the most common form of congenital heart disease in implantable cardioverter-defibrillator (ICD) recipients, yet little is known about the value of ICDs in this patient population. Methods and Results— We conducted a multicenter cohort study in high-risk patients with Tetralogy of Fallot to determine actuarial rates of ICD discharges, identify risk factors, and characterize ICD-related complications. A total of 121 patients (median age 33.3 years; 59.5% male) were enrolled from 11 sites and followed up for a median of 3.7 years. ICDs were implanted for primary prevention in 68 patients (56.2%) and for secondary prevention in 53 (43.8%), defined by clinical sustained ventricular tachyarrhythmia or resuscitated sudden death. Overall, 37 patients (30.6%) received at least 1 appropriate and effective ICD discharge, with a median ventricular tachyarrhythmia rate of 213 bpm. Annual actuarial rates of appropriate ICD shocks were 7.7% and 9.8% in primary and secondary prevention, respectively (P=0.11). A higher left ventricular end-diastolic pressure (hazard ratio 1.3 per mm Hg, P=0.004) and nonsustained ventricular tachycardia (hazard ratio 3.7, P=0.023) independently predicted appropriate ICD shocks in primary prevention. Inappropriate shocks occurred in 5.8% of patients yearly. Additionally, 36 patients (29.8%) experienced complications, of which 6 (5.0%) were acute, 25 (20.7%) were late lead-related, and 7 (5.8%) were late generator-related complications. Nine patients died during follow-up, which corresponds to an actuarial annual mortality rate of 2.2%, which did not differ between the primary and secondary prevention groups. Conclusions— Patients with tetralogy of Fallot and ICDs for primary and secondary prevention experience high rates of appropriate and effective shocks; however, inappropriate shocks and late lead-related complications are common.

Value of Programmed Ventricular Stimulation After Tetralogy of Fallot Repair A Multicenter Study

Background—Studies have consistently shown that ventricular tachycardia (VT) and sudden cardiac death (SCD) complicate the long-term outcome after tetralogy of Fallot repair, yet the diagnostic and predictive value of electrophysiological testing in this population is uncertain. Methods and Results—A multicenter cohort of 252 patients with repaired tetralogy of Fallot undergoing programmed ventricular stimulation was followed up for 18.5±9.6 and 6.5±4.5 years after corrective surgery and electrophysiological testing, respectively. Clinical VT and/or SCD occurred in 24.6%. Sustained monomorphic VT and polymorphic VT were induced in 30.2% and 4.4%. Including polymorphic VT in the definition of inducibility improved sensitivity (66.1±6.0% versus 77.4±5.3%, P = 0.0082) with a marginal reduction in specificity (81.6±2.8% versus 79.5±2.9%, P = 0.0455). Positive and negative predictive values were 55.2±5.3% and 91.5±2.2%. Independent risk factors for inducibility were age at study ≥18 years (OR, 3.3), palpitations (OR, 2.8), prior palliative surgery (OR, 3.1), modified Lown criteria ≥2 (OR, 5.6), and cardiothoracic ratio ≥0.6 (OR, 3.3). Event-free survival rates in noninducible and inducible patients at 1, 5, 10, and 15 years were 97.9%, 92.8%, 89.3%, and 89.3% versus 79.4%, 62.6%, 58.7%, and 50.3%, respectively (P < 0.0001). Both inducible monomorphic VT [relative risk (RR), 5.0; P = 0.0002] and polymorphic VT (RR, 12.9; P < 0.0001) predicted future clinical VT and SCD. In a multivariate analysis, inducible sustained VT was an independent risk factor for subsequent events (RR, 4.7; 95% CI, 1.2 to 18.5; P = 0.0268). Conclusions—Programmed ventricular stimulation is of diagnostic and prognostic value in risk stratifying patients with repaired tetralogy of Fallot. In this patient population, inducible sustained polymorphic VT should not be disregarded as nonspecific.

Arrhythmia Burden in Adults With Surgically Repaired Tetralogy of Fallot A Multi-Institutional Study

Background— The arrhythmia burden in tetralogy of Fallot, types of arrhythmias encountered, and risk profile may change as the population ages. Methods and Results— The Alliance for Adult Research in Congenital Cardiology (AARCC) conducted a multicenter cross-sectional study to quantify the arrhythmia burden in tetralogy of Fallot, to characterize age-related trends, and to identify associated factors. A total of 556 patients, 54.0% female, 36.8±12.0 years of age were recruited from 11 centers. Overall, 43.3% had a sustained arrhythmia or arrhythmia intervention. Prevalence of atrial tachyarrhythmias was 20.1%. Factors associated with intraatrial reentrant tachycardia in multivariable analyses were right atrial enlargement (odds ratio [OR], 6.2; 95% confidence interval [CI], 2.8 to 13.6), hypertension (OR, 2.3; 95% CI, 1.1 to 4.6), and number of cardiac surgeries (OR, 1.4; 95% CI, 1.2 to 1.6). Older age (OR, 1.09 per year; 95% CI, 1.05 to 1.12), lower left ventricular ejection fraction (OR, 0.93 per unit; 95% CI, 0.89 to 0.96), left atrial dilation (OR, 3.2; 95% CI, 1.5 to 6.8), and number of cardiac surgeries (OR, 1.5; 95% CI, 1.2 to 1.9) were jointly associated with atrial fibrillation. Ventricular arrhythmias were prevalent in 14.6% and jointly associated with number of cardiac surgeries (OR, 1.3; 95% CI, 1.1 to 1.6), QRS duration (OR, 1.02 per 1 ms; 95% CI, 1.01 to 1.03), and left ventricular diastolic dysfunction (OR, 3.3; 95% CI, 1.5 to 7.1). Prevalence of atrial fibrillation and ventricular arrhythmias markedly increased after 45 years of age. Conclusions— The arrhythmia burden in adults with tetralogy of Fallot is considerable, with various subtypes characterized by different profiles. Atrial fibrillation and ventricular arrhythmias appear to be influenced more by left- than right-sided heart disease.

Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary Hypertension

Background—Although pulmonary thromboendarterectomy is increasingly successful for the definitive treatment of chronic thromboembolic pulmonary hypertension (CTEPH), not all patients have surgically accessible disease. Others are poor surgical candidates because of comorbid illness. Therefore, for selected patients, we defined and implemented an alternative interventional strategy of balloon pulmonary angioplasty (BPA). Methods and Results—Eighteen patients (mean age, 51.8 years; range, 14 to 75 years) with CTEPH underwent BPA; they averaged 2.6 procedures (range, 1 to 5) and 6 dilations (range, 1 to 12). Selection of pulmonary artery segments for dilation required (1) complete occlusion, (2) filling defects, or (3) signs of intravascular webs. After an average of 36 months of follow-up (range, 0.5 to 66 months), the average New York Heart Association class improved from 3.3 to 1.8 (P <0.001), and 6-minute walking distances increased from 209 to 497 yards (P <0.0001). Pulmonary artery mean pressures decreased from 43.0±12.1 to 33.7±10.2 mm Hg (P =0.007). Eleven patients developed reperfusion pulmonary edema; 3 required mechanical ventilation. Conclusions—BPA reduces pulmonary artery hypertension in patients with CTEPH and is associated with long-term improvement in New York Heart Association class and 6-minute walking distances. BPA is a promising interventional technique that warrants randomized comparison with medical therapy in CTEPH patients who are not surgical candidates.