Novel acquisitions in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by chronic obstruction of major pulmonary arteries with organized thrombi that appear as rings, webs, and as subtotal or total vascular occlusions (Figure 1). The condition is thought to be a late sequela of acute pulmonary embolism, although pulmonary revascularization through thrombolysis at the time of the acute event was not able to prevent CTEPH.1 In addition, a concomitant, ‘secondary’ small-vessel arteriopathy has been histologically proven,2 and has been associated with worse hemodynamics and poorer outcomes. While modern imaging is indispensable for the diagnosis of the typical CTEPH vascular lesions there is no direct imaging of microvascular changes possible today. This is a limitation in clinical practice. However, secondary microvasculopathy (or postobstructive vasculopathy), as well as systemic vascularization of the lung, regressed after pulmonary artery reperfusion in several animal models.3 These data raise the hope that through effective mechanical treatments secondary microvasculopathy and bronchial arterial collateralization of CTEPH may be reversible. This hypothesis is corroborated by the observation that successfully operated patients regain almost normal hemodynamics and exercise capacity, and hemoptysis disappears. Similar gain is reported from Japanese balloon pulmonary angioplasty (BPA) interventionists who promote interventions with the goal to reach haemodynamics beyond normalisation at rest.4 Digital subtraction pulmonary angiogram of a case example of chronic thromboembolic pulmonary hypertension with typical major vessel pulmonary artery lesions. Since 1965, pulmonary endarterectomy (PEA), the surgical removal of major vessel obstruction has been the state-of-the-art treatment option for CTEPH, and has evolved to a surgical mainstay treatment with low mortality in expert centers.5 However, only ∼50% of patients were candidates for PEA, thus, leaving half of the CTEPH population with no specific treatment option. In 2001, one report from the US suggested that mechanical treatment may be able by percutaneous techniques,6 but results were still unsatisfactory, and safety was an issue. In 2013, Japanese interventionists reported a refined technique of BPA,7 bringing dramatic improvements to the no-option population, including a broad group of patients that may be eligible for both mechanical treatments. In addition, the first successful clinical trial of an effective oral vasodilator therapy for nonoperable CTEPH, or residual pulmonary hypertension (PH) after PEA was published,8 followed by randomized controlled proof of the efficacy of a subcutaneous prostacyclin analogue in severe CTEPH.9 Since these milestones, quality of life and survival of CTEPH have dramatically improved. While the CTEPH registry report of 2016 highlighted significantly better survival of operable patients,10 this difference has been decreasing. The final milestone for the improvement of CTEPH care was the agreement that combining all three treatment strategies, PEA, BPA, and medical,5 one may be able to reach normal resting haemodynamics and quality of life for patients. Figure 2 summarizes novel acquisitions in group 4 PH as depicted in the most recent ESC guidelines on the diagnosis and treatment of PH.5 First, Figure 2 illustrates and clarifies novel terminology in diagnosis group 4 of the current guidelines, where chronic thromboembolic pulmonary disease (CTEPD) has been established as the overarching term to define cases of CTEPD with PH (CTEPH), and cases of CTEPD without PH. However, the key term remains CTEPH because CTEPD without PH occurs in no more than 3% of cases, and is rare given the prevalence estimate of CTEPH of roughly 50 cases per million.5 The hemodynamic definition of CTEPH includes a mPAP >20 mmHg, PVR >2WU, and mPAWP ≤15 mmHg,5 however, recent data suggest that up to 1/3 of patients with CTEPH suffers from concomitant left heart disease, with elevated filling pressures.11 Modern diagnosis and treatment of chronic thromboembolic pulmonary hypertension. The algorithm illustrates a central role of the Multidisciplinary Team in the diagnosis and treatment of CTEPH. PEA = pulmonary endarterectomy, BPA = balloon pulmonary angioplasty, Medical treatments = treatment with specific pulmonary vasodilators. The second novel acquisition is the emphasis on CTEPH centers that are clearly defined as tertiary care centers offering multidisciplinary teamwork with access to cardiology, pneumonology, cardiothoracic surgery, nursing specialist care, interventional cardiology and radiology, expert imaging, case managers, data managers, clinical trialists, and social workers. An extended MDT offers pediatrics, adult congenital heart disease, pathology, particularly pathology of the lung, genetics, basic research, physiotherapy, psychology, intensive care, mechanical circulatory support, rheumatology, hepatology, dermatology, gynecology, pregnancy heart team support, transplantation, anesthesiology, and palliative care. The guidelines recommendation of a multidisciplinary team (MDT) as a prerequisite in patient management guarantees a multimodality treatment approach,5 taking advantage of access to any experts that may be needed in the individual case. CTEPH is a condition that occurs mainly in the elderly, thus making interdisciplinary management particularly important. The first MDT decision clarifies the initial treatment strategy (Figure 2), choosing between PEA, BPA, and medical therapy. Initial therapy can be a single mechanical option, or combinations thereof, with sequential or even simultaneous application of individual treatments. Follow-ups are usually between 3 and 6 months after PEA, or after the final BPA session. After reassessment, the MDT provides a second treatment decision, that includes now an option of ‘no further measure,’ or conservative strategy, including de-escalation or termination of medical treatments if functional capacity is restored, all technically accessible vascular lesion addressed, and patient satisfied. While there are three treatment options and their combinations available, little objective data exist to support particular pathways. New insight may be derived soon from a study investigating combination therapy prior to BPA, compared with monotherapy (IMPACT CTEPH, ClinicalTrials.gov Identifier NCT04780932), but no data exist on the combination of mechanical and medical treatments that are placebo-controlled because of the concern that those studies may be unethical. In summary, the key novelty in CTEPH care has become the treatment approach that is now determined by a multidisciplinary group offering three complementary strategies: PEA, BPA, and effective pulmonary vasodilator therapies. It is to be expected that registry data will soon document improvement of survival compared with historical data. No new data were generated or analysed in support of this article. All authors declare no funding for this contribution.