Cohort Definition Name: “Chronic Thromboembolic Pulmonary Hypertension”
Contributor name: Joel N. Swerdel
Contributor OrcId: 0000-0001-9491-2737
Logic Description: First occurrence of Chronic Thromboembolic Pulmonary Hypertension.
Recommended study application: outcome, indication
Assertion statement: This cohort definition was executed on at least one real person-level observational health data source and resulted in a cohort with at least 1 person.
Submitted cohort definition:
cteph.txt (49.8 KB)
Target Clinical Description
Overview
CTEPH is a rare and severe form of PH.
CTEPH is characterized by macroscopic thromboembolic lesions and microscopic pulmonary vasculopathy. The management options for CTEPH target different pathogenic manifestations in different parts of the pulmonary vascular bed and include surgical (pulmonary endarterectomy [PEA]), interventional (balloon pulmonary angioplasty [BPA]), and medical treatment. Since most patients have proximal and/or distal vascular lesions as well as microvasculopathy, a multimodal approach and combination of treatment regimens is likely to be needed in most patients. Medical treatment in CTEPH targets microvasculopathy that resembles the PAH lesions.
The field is driven by guidelines and recommendations from various international and local scientific societies. The next milestones will be the 2022 ESC/ERS guidelines on PH, the International Conference on CTEPH (ICC) (San Diego) in Q3 2023 and the 7th World Symposium on Pulmonary Hypertension (WSPH) in 2024.
Presentation
Initially there are no or only unspecific clinical signs and symptoms in patients with CTEPH, making an early diagnosis challenging. Signs of right heart failure (dyspnea on exertion, peripheral edema, cyanosis, fatigue) become evident in advanced disease. The clinical course in CTEPH reflects the progressive increase in PVR which characterizes this condition. Progressive PH, right ventricular (RV) dysfunction, and death ensue if the condition is left untreated.
CTEPH patients have heterogenous clinical profiles (Appendix 5) depending on whether they are technically inoperable, medically inoperable/not operated, or with persistent/recurrent CTEPH. This may lead to various indications or responses to medical therapy.
As in PAH, symptoms are not specific and a lack of awareness of this rare disease leads to low levels of suspicion. The diagnosis of CTEPH is delayed by an average of 14 months from the onset of symptoms, and patients typically present with advanced disease. At the same time, early diagnosis and referral to a CTEPH expert center are critical to discuss multimodal management and optimize outcomes. Non-adherence to the CTEPH diagnosis and treatment guidelines (Galiè N et al. 2015, Galiè N et al. 2016, Galiè N et al. 2019) is documented.
Assessment
The diagnosis of CTEPH is based on hemodynamic and imaging findings obtained after at least 3 months of effective anticoagulation in order to differentiate this condition from subacute pulmonary embolism (PE). A normal ventilation/perfusion (V/Q) scan effectively excludes CTEPH and it remains the preferred initial imaging test (Galiè N et al. 2015, Kim NH et al. 2019, Delcroix M et al. 2020). Patients with suspected CTEPH should be referred to an expert CTEPH center for confirmation of the diagnosis.
Indeed, CTEPH is a complex disease requiring a multimodal and individualized approach to treatment at expert centers. Diagnosis, as well as advanced therapy, involves a multidisciplinary team located at one of the few CTEPH expert centers. Beyond the PH specialist, these multidisciplinary teams include surgeons experienced in PEA, interventional cardiologists or radiologists experienced in BPA, and CTEPH-trained radiologists.
Imaging plays a key role in suspicion, diagnosis and treatment of CTEPH (Galiè N et al. 2015, Galiè N et al. 2016). CTEPH is usually considered at two time points: (1) when presenting with acute pulmonary embolism (PE), if radiological signs suggest CTEPH on the computed tomography pulmonary angiography (CTPA) performed to diagnose PE, or (2) more classically, when dyspnea or functional limitations persist in the clinical course of PE. A third condition could concern asymptomatic patients with risk factors for CTEPH or a high pre-test probability (Delcroix M et al. Eur Respir J 2020).
In real-world clinical practice, use of imaging is not optimal. Imaging of the pulmonary vasculature (with CTPA, MRI or conventional pulmonary angiography, dual energy CT angiography or digital subtraction angiography) is not performed in one-third of patients, in the US and EU (Janssen - Data on file). The situation is possibly worse in countries with less easy access to imaging.
A history of PE is found in 75% of CTEPH patients (Pepke-Zaba J et al. 2011). Radiologic signs of CTEPH are already present on the first available CTPA of the index PE diagnosis in the majority of CTEPH patients. Some CTEPH cases are even misclassified as an acute PE (Ende-Verhaar Y.M. et al. 2018, Ende-Verhaar YM et al. 2019). In addition, some CTPA signs, present at the time of the index PE, may predict CTEPH development (Lorenz G et al. 2020). Recognition of these signs can reduce the time to the definite CTEPH diagnosis. These signs have been incorporated in the 2019 ESC/ERS guidelines on PE (Konstantinides SV et al. 2019, Konstantinides SV et al. 2020) with the recommendation that pre-existing CTEPH should not be missed in patients investigated for suspected acute PE. Non-expert radiologists frequently miss CTEPH findings
Features of CTEPH on CTPA are subtle and often difficult to recognize. Interpretation of CTPA for the diagnosis of CTEPH requires significant expertise, best found in CTEPH expert centers.
Post-PE patients (and some patients with concomitant chronic disease and conditions) are a population at risk of developing CTEPH. As described in the 2019 ESC/ERS guidelines dedicated to PE (Konstantinides SV et al. 2019, Konstantinides SV et al. 2020), PE is the third most common acute cardiopulmonary disease after coronary artery disease and stroke. But CTEPH is a rare complication of PE with an incidence of 3% in PE survivors. PE patients are very frequently lost to follow-up after the acute phase at an average of 8 months.
A recent study on PE follow-up and CTEPH diagnosis called FOCUS) (Valerio L et al. 2022) conducted in Germany was just been published: it concludes that the cumulative 2-year incidence of CTEPH was 2.3% among a cohort of adult consecutive patients with confirmed acute symptomatic PE.
Plan
The management of CTEPH and PAH is different, with a more centralized and multidisciplinary approach in CTEPH. Treatment of CTEPH does not solely rely on medical therapy.
PEA remains the gold standard treatment for eligible patients. In-hospital mortality is low (< 5% in high-volume centers with trained surgeons). Residual PH after PEA is frequent (overall estimate of around 50%). It affects the long-term outcome of patients after PEA and represents a target for medical therapies and BPA (Delcroix M et al. 2020). There is no generally accepted definition of residual PH after PEA.
In patients who are ineligible for PEA (due to distal occlusions or unfavorable benefit/risk ratio), there is increasing experience with BPA, with more countries having BPA facilities. In addition, long-term results after BPA (up to 8 years) are now available. Safety and efficacy of BPA correlate with center experience (> 100 patients/year) and, like for PEA, a learning curve has been described. With such a development, it is expected that medical therapy will be increasingly combined with BPA.
Treatment goals for medical therapy and BPA in CTEPH are not defined. Additionally, there is lower use of combination medical therapy in CTEPH compared to PAH. This may be due to the recent availability of approved drugs in CTEPH and to the lack of guidance for escalation such as the risk assessment tools used in PAH.
With regards to medical therapy (targeting microvasculopathy) in inoperable CTEPH patients or in patients with residual PH after PEA:
One drug, riociguat (Adempas®), is approved in most countries for CTEPH (since October 2013 in the US and March 2014 in Europe). It is likely to be considered as the standard of care (SoC) in most countries and therefore, to be combined with macitentan. The absence of a drug-drug interaction with riociguat has been documented for macitentan 10 mg and macitentan 75 mg. Post-marketing safety (PMS) data from the EXPERT registry are available in 956 CTEPH patients (Ghofrani H-A et al. 2021) and confirm that the safety profile of riociguat in CTEPH is consistent with the known profile of the drug.
In April 2020, a hybrid formulation of subcutaneous (s.c.) treprostinil (Trepulmix®) was approved for CTEPH in Europe. Trepulmix® is commercially available in Germany, Italy, Spain, Latvia and the UK.
Prognosis
CTEPH is a chronic and life-shortening condition. CTEPH patients’ clinical profiles are highly variable (Appendix 5). The current categorization is linked to operability and treatment response: i.e., whether they are technically inoperable, medically inoperable, operable but not operated for other reasons, experience persistent/recurrent PH after mechanical intervention, etc. These different subgroups of patients have different outcomes.
References
Delcroix M et al. Eur Respir J 2020;57:2002828
Ende-Verhaar Y.M. et al. Journal of Thrombosis and Haemostasis 2018;16:2168–74.
Ende-Verhaar YM et al. The Journal of Heart and Lung Transplantation 2019;38:731–8.
Galiè N et al. Eur Heart J 2016;37:67–119
Galiè N et al. Eur Respir J 2019;53:1802148
Galiè N et al. N Engl J Med 2015; 373:834-44
Ghofrani H-A et al. Respiratory medicine 2021;178:106220.
Janssen - Data on file;Monitor CTEPH patient chart study H1 2019 EU 4 and US
Kim NH et al. Eur Respir J2019; 53: 1801915
Konstantinides SV et al. Eur Respir J 2019;54:1901647.
Konstantinides SV et al. Eur. Heart J. 2020;41:543–603
Lorenz G et al. AJR Am J Roentgenol 2020;215:800–6.
Pepke-Zaba J et al. Circulation 2011;124:1973-81
Simonneau G et al. Eur Respir J 2019;53:1801913
Valerio L et al. Eur. Heart J. 2022; 00, 1–12;41:543–603