Chronic thromboembolic pulmonary hypertension (CTEPH) is in the group 4 pulmonary hypertension (PH) clinical classification1, alongside other forms of vascular obstruction. It is defined in the presence of a precapillary hemodynamic phenotype resulting from incomplete resolution and fibrotic transformation of thromboembolic material in the pulmonary arteries after at least three months of effective anticoagulation. Its etiopathogenesis is likely to be one or more episodes of acute pulmonary embolism (PE), and possible phenomena of in situ pulmonary thrombosis may also be considered. The correct identification of the nosological entity, which is often underdiagnosed, is of utmost importance, given the curative potential of treatment. Historically, the long-term prognosis of this disease has been poor, with an estimated five-year survival rate in the absence of adequate treatment of about 10%2. Pulmonary endarterectomy (PEA) has emerged as the gold standard approach to CTEPH in patients with a surgically accessible fibro-thromboembolic burden3, leading to proven symptomatic and prognostic benefits4. It should be noted that both the imaging techniques for defining operability and the surgical intervention process should be carried out at centers with proven experience in the diagnosis and treatment of PH5,6 with operative mortality rates <5% and significant improvement in symptoms, functional capacity and hemodynamic parameters7–9.

This study aims to report the initial experience of a Portuguese center for the treatment of PH analyzing medium-term survival and functional, hemodynamic, and right ventricular function results in patients undergoing PEA.

For the first time in Portugal, this prospective observational study describes the initial experience of patients with CTEPH followed at a national center (Portugal) for the treatment of PH undergoing PEA at an international reference surgical center (United Kingdom).

This study attested to the safety and efficacy, in terms of survival and clinical and hemodynamic improvement, of PEA performed at a high-volume surgical center. Of the three specific treatments for CTEPH, PEA is the one with the highest evidence of efficacy5,14–16, with a class of recommendation I, level of evidence C, in operable patients6. European recommendations and the 6th World Symposium on Pulmonary Hypertension differentiating between operable and non-operable CPTH. However, in clinical practice this distinction is subjective and determined by local surgical experience and practice. Since the definition of operability is a major factor in the assessment of patients with CTEPH, it should be reached within multidisciplinary input at centers with proven experience.

In the largest published study with patients undergoing PEA, mPAP was reduced from 46 mmHg to 26 mmHg and PVR from 9.0 uW to 3.2 uW8. The magnitude of hemodynamic improvement is very similar to that reported in the present study and at the center where patients were operated. This study achieved the largest long-term follow-up series, attesting to the excellent post-PEA survival of patients with CTEPH4. In that study, residual PH (mPAP ≥25 mmHg at six months after PEA) was a frequent finding at 51%, a rate similar to that of our series (56% (n=15)). Persistent PH after surgery has been reported in 11% to 35% of patients in other series, with important prognostic implications15–20. It should be noted, however, that there is still no unanimity regarding the definition of residual PH after PEA, either in terms of absolute MPAP values or in terms of the timing of assessment. In our study, factors associated with the persistent PH after surgery were longer delay from the onset of symptoms to diagnosis and from diagnosis to PEA, older age, and severity of respiratory failure. This highlights the importance of a timely diagnosis and intervention, both of which are essential to reduce the development and progression of vasculopathy in areas without fibrothrombotic burden (“reactive” or “secondary” arteriopathy).

Even though a significant number of patients maintained the hemodynamic criteria for PH after surgery, there was a significant improvement in terms of functional capacity. In a large international prospective registry of CPEAPH, 6MWT increased from 362 to 459 m in 386 operated patients9. In long-term follow-up of 880 operated patients in the United Kingdom, 6MWT increased from 260 to 353 m and WHO FC (% I/II/III/IV) improved from 0/9/68/23 to 34/47/15/04. In our experience, we found a similar improvement in functional capacity after PEA as in the aforementioned studies: 6MWT increased from 294 to 366 m and WHO FC (% I/II/III/IV) improved from 0/11/74/15 to 48/41/11/0 (Figure 2).

Despite the undeniable efficacy of PEA in patients with CTEPH, the procedure is complex and is associated with variable in-hospital mortality rates, which can reach 16%18,21,22. Accumulated experience and the tendency to concentrate the procedure in high-volume centers have resulted in a proven significant reduction in in-hospital mortality, which lies at <2.5%, identical to the reference center for the patients included in this study4. Results from the largest prospective international CTEPH registry show that in centers with less than ten procedures per year, in-hospital and long-term mortality rates are double those of high-volume centers23. In our study, there was no mortality. During follow-up, there was one death related to disease progression, despite initial improvement after surgery. This patient’s variables were considered independent predictors of long-term mortality: poor functional capacity, high mPAP, mRAP and PVR, low cardiac index and the need for early initiation of pulmonary vasodilator therapy after surgery24,25. In the international prospective registry of CTEPH, perioperative complications were recorded in 49.2% of cases, a higher rate than that observed in our patient population, despite the small sample size. The complications reported in this analysis are unanimously found in other series. One case of non-traumatic subdural hematoma was documented, a complication recently described as underdiagnosed in patients undergoing PEA26.

Regarding a key point of surgery — the deep hypothermic circulatory time, sometimes requiring a subtle compromise between adequate endarterectomy versus postoperative morbidity. An increase in circulatory arrest time is associated with an increased incidence of neurological complications27 but a greater reduction in PVR21,22. In the international prospective registry of CTEPH, the median duration of circulatory arrest was only 35 minutes9, similar to our population — 34 minutes.

Chronic thromboembolic pulmonary hypertension has been described according to a tri-compartmental disease model: 1) a component of proximal vascular disease that can be approached via PEA; 2) a component of subsegmental thrombotic obstructive disease sometimes not surgically accessible and a potential target for pulmonary balloon angioplasty28,29; 3) a component of small vessel vasculopathy, histologically similar to pulmonary arterial hypertension, resulting from blood hyperflow in areas without fibrothrombotic obstruction and the main target of medical vasodilator therapy30,31. In our series, most (85%) patients had proximal disease (types I and II — Table 2), and the remainder were characterized by more distal disease, but still considered surgically approachable. The operability rate (93%) in this case was much higher than that commonly reported in different series in which it ranges from 10% to 50%32. However, diagnostic advances and growing surgical experience have been important in redefining the distal limits of PEA; at specialized centers, surgery can be successfully performed in selected patients with distal disease. Therefore, published inoperability rates may overestimate actual overall inoperability. As an example, in the CHEST-1 study the central adjudication committee (whose members perform more than 50 PEAs per year) doubled the operability rate relative to that considered by local adjudication committees33.

Despite the small number (n=4), the presence of distally distributed disease was associated with worse hemodynamic outcome and persistent PH after surgery, as described in several studies11,22,34. Perioperative complications were not more frequent in this group. It should be noted that the most recent developments in PEA require more refined definitions of operable CTEPH. More distal obstructions, namely at the subsegmental or even distal segmental level may be considered inoperable at less experienced centers. However, a highly experienced team may consider such cases operable. It is the opinion of high-volume centers that all patients with CTEPH, including those with distal disease, should be evaluated for PEA5.

The aforementioned anatomical distribution of CTEPH provides the rationale for the use of other circulatory optimization strategies. Distal vasculopathy in CTEPH, either thrombotic or ‘reactive’ to hyperflow in areas without thrombotic burden, has been the subject of studies with drugs targeting pulmonary arterial hypertension. Vasodilator therapy is indicated in symptomatic patients with inoperable CTEPH or residual/recurrent PH after PEA. The use of vasodilator drugs in operable CTEPH prior to PEA may improve hemodynamics before the procedure35–37, but does not appear to affect prognosis and hemodynamics post-surgery38. Despite the absence of evidence to support this practice, several centers resort to pharmacological bridge to surgery with the goal of hemodynamic and functional improvement6. The group from the University of California (San Diego, USA) published that about 45% of patients with operable CTEPH were treated with at least one vasodilator drug before referral for PEA8. In the international prospective CTEPH registry, 29% of operated patients received bridge therapy. These patients had worse FC and were more hemodynamically compromised compared to those not medicated. At our center, we medicated most patients (93%; n=25) prior to surgery, based on functional status and hemodynamic outcomes. This practice, currently no longer used, reflects, to some extent, the modus operandi of a center where PEA was not previously considered.

At about four to six months after PEA, we began specific pulmonary vasodilator therapy with at least one drug in 44% (n=12) of patients, a higher rate than that reported by the largest long-term follow-up series of CTEPH patients operated on (21%)4. This decision was based on functional (such as WHO FC and 6MWT) and hemodynamic parameters (mPAP and mRAP), which have been independently associated with the start of therapy.

Recent randomized clinical trials have shown that the soluble guanylate cyclase stimulator riociguate and the endothelin receptor antagonists bosentan and macitentan provided short- to medium-term symptomatic, hemodynamic and functional improvement30,31,39,40. In the CHEST-1 study, mPAP and PVR were reduced by about 10% and 33%, respectively, while 6MWT increased by just over 10% in the riociguate arm and 33% of patients reported a one-point improvement in FC. The safety and efficacy of riociguate appears to extend beyond 2 years40,41, although benefits in long-term mortality have not yet been demonstrated. A very similar positive effect on PVR was demonstrated in the MERIT-1 study with the use of macitentan31. These drugs can be used as monotherapy or in combination with other classes (off-label) — phosphodiesterase inhibitors or prostanoid analogues. However, it must be noted that their effects do not modify the underlying thromboembolic/fibrotic mechanical obstructions and must be taken ad eternum, which entail significant costs and some side effect-related morbidity.

With regard to anticoagulant therapy, vitamin K antagonists are the classically indicated drugs in patients with CTEPH, and there are not many safety, and efficacy data with DOACs, despite their increasing and widespread use. A recent retrospective study by the Papworth group, the largest to date on the use of anticoagulants in CTEPH (794 patients after PEA) found that in 2017-2018, 55% of the population was medicated with DOACs42, a rate comparable to other centers43, including the one in the present study (48%). They found that post-PEA functional, hemodynamic, incidence of bleeding and survival outcomes were independent of the type of anticoagulant. There was, however, a higher incidence of recurrent venous thromboembolism with the use of direct oral anticoagulants (DOACs) (4.62% vs. 0.76%/person-year; p=0.008). Further studies in this area will be needed to define the best anticoagulation strategy in patients with CTEPH.

Patients with CTEPH often require LTOT, as the mechanisms of respiratory failure are multifactorial — low cardiac output state and ventilation-perfusion mismatch. In our series, PEA led to a significant reduction in the number of patients on LTOT — 14 vs seven patients. Additionally, the presence of LTOT pre-PEA was associated with persistent PH. It should be noted that there was a dissociation between hemodynamic improvement and respiratory failure, the former being earlier, as described in other studies44,45. Ishida et al. observed that although 92% of patients returned to WHO functional classes I and II post-PEA, 37% would still be dependent on LTOT25. Potential underlying mechanisms include the presence of post-surgery lung restriction and the greater latency in restoring ventilation/perfusion in previously obstructed areas due to reperfusion edema and the effect of ‘coronary steal’ from obstructed areas and with higher PVR for unobstructed areas.

The incidence, prevalence, and epidemiology of CTEPH in Portugal are not yet widely known. These data are difficult to obtain because it is an underdiagnosed46 disease, which reflects the non-specific characteristics of the signs and symptoms, limited recognition of the disease and inefficient application of diagnostic tests23,47,48. Registry data suggest a prevalence in the general population of 3-30/million49. In the first50 Portuguese multicenter prospective registry of patients with PH and CTEPH, the cases of CTEPH represented 41.8% of the population.

In this study, the median times from symptom onset to diagnosis and from diagnosis to surgery were 26 (14-53) and 16 (8-48) months, respectively. To provide the best approach for patients with CTEPH, it is essential to increase the medical profession’s awareness of the disease, thus avoiding diagnostic and therapeutic delays.

Classically, CTEPH is considered a complication of acute PE, with a described prevalence of between 2% and 4% after the event14,44,51. However, not all patients with CTEPH have a history of acute PEA. In our series, 16 (59%) patients reported a history of acute PE. A large prospective international CTEPH registry reported that 75%-80% of included patients had a history of acute PE23,47. However, this frequency is probably overestimated, since the diagnosis of acute PE has not been properly documented in a significant number of patients. Additionally, it is hypothesized that several cases described as acute PE could be early manifestations of CTEPH.

The main limitation of this study was the difficulty in compiling clinical data, since it took place at two centers located in different countries. However, this is the only study to date that presents an international partnership in the multidisciplinary treatment of this disease.

A Portuguese center for the surgical treatment of CTEPH has recently been appointed by the Portuguese health authority. However, there are still no published objective data on the post-surgery hemodynamic results, the essential gold standard of the efficacy and quality of surgery in CTEPH, to allow for important comparison to be made by our scientific community. This will allow clinicians who follow these patients to decide which is the best solution in each case.

National experience of cooperation with another country shows the safety of the protocol paving the way for the Portuguese center — the same may be applied in Portugal, now as a surgical center, enabling referral from the Portuguese islands and other countries, in particular, the Portuguese-speaking African countries, as is already the tradition in Portugal.

The literature review and current experience demonstrate that PEA performed at a highly differentiated and experienced surgical center is a safe procedure with a very favorable mid-term impact on functional, hemodynamic, and right ventricular function parameters in patients with operable CTEPH.

The first stage of surgical success begins with early diagnosis of CTEPH, targeted therapy and patient stabilization to allow for surgery to take place. The role of a differentiated medical center is again critical for morbidity and mortality outcomes.

This study shows that it is possible for clinical centers specialized in the treatment of PH without PEA differentiation, to refer patients safely and effectively to an international surgical center where air transportation is necessary.

The authors have no conflicts of interest to declare.