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Follow-up after acute pulmonary embolism (PE) is important to assess recovery, consider the need for on-going anticoagulation and identify chronic thromboembolic pulmonary hypertension (CTEPH), a rare but serious complication of PE. 16 dilemmas in the follow-up of acute PE were identified by a steering committee of four pulmonologists and a haematologist with interest in PE and/or CTEPH. Current literature was reviewed and a practical approach suggested based on expert consensus. Dilemmas discussed included: (1) how to manage a breathless patient; (2) what to do if CTEPH is suspected; (3) the difference between CTEPH and post-PE syndrome, (4) testing for thrombophilia, (5) when to investigate for cancer, (6) anticoagulation duration and dose, (7) approaches to discussions and decision-making with respect to anticoagulation, (8) use of aspirin and whether antiplatelet therapy should be stopped during anticoagulation and (9) advice for patients on discharge from hospital at 3 months and information for first-degree relatives. Given the occurrence of complications that may require assessment, follow-up of patients post-PE should be systematic and consider the individual needs of the patient.

The aims of this study were to investigate the medication adherence of patients on pulmonary hypertension (PH)-targeted therapies and uncover factors that might influence adherence values. Patients taking at least one specialist medicine (sildenafil, tadalafil, bosentan, ambrisentan, iloprost, epoprostenol, treprostinil) completed a Morisky Medication Adherence Scale-8 (MMAS-8) questionnaire. Participants’ MMAS-8 scores were used to estimate overall medicine adherence. Potential adherence co-factor data were collected from patient databases and hospital discharge summaries. The MMAS-8 questionnaire was completed by 263 patients (mean age = 61.6 ± 14.8 years, 70.6% women). Data from MMAS-8 showed that 47.9% reported high adherence, 40.3% moderate adherence, and 11.8% low adherence. Factors associated with adherence as measured by the MMAS-8 included: older age; taking monotherapy; and having a higher number of co-morbidities or concurrent medicines. Higher administration frequency, greater length of time on targeted therapy, and use of a compliance aid had a negative association with adherence. Overall adherence to PH specialist medicines is relatively high but a proportion of patients report sub-optimal adherence behavior. A number of factors may help to recognize susceptible patients.

Several patient-reported outcome measures have been developed to assess health status in pulmonary arterial hypertension. The required change in instrument scores needed, to be seen as meaningful to the individual, however remain unknown. We sought to identify minimal clinically important differences in the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and to validate these against objective markers of functional capacity. Minimal clinically important differences were established from a discovery cohort (n = 129) of consecutive incident cases of idiopathic pulmonary arterial hypertension with CAMPHOR scores recorded at treatment-naïve baseline and 4–12 months following pulmonary arterial hypertension therapy. An independent validation cohort (n = 87) was used to verify minimal clinically important differences. Concurrent measures of functional capacity relative to CAMPHOR scores were collected. Minimal clinically important differences were derived using anchor- and distributional-based approaches. In the discovery cohort, mean (SD) was 54.4 (16.4) years and 64% were female. Most patients (63%) were treated with sequential pulmonary arterial hypertension therapy. Baseline CAMPHOR scores were: Symptoms, 12 (7); Activity, 12 (7) and quality of life, 10 (7). Pulmonary arterial hypertension treatment resulted in significant improvements in CAMPHOR scores (p < 0.05). CAMPHOR minimal clinically important differences averaged across methods for health status improvement were: Symptoms, –4 points; Activity, –4 points and quality of life –3 points. CAMPHOR Activity score change ≥minimal clinically important difference was associated with significantly greater improvement in six-minute walk distance, in both discovery and validation populations. In conclusion, CAMPHOR scores are responsive to pulmonary arterial hypertension treatment. Minimal clinically important differences in pulmonary hypertension-specific scales may provide useful insights into treatment response in future clinical trials.

This manuscript on endpoints incorporates the broad experience of members of Pulmonary Vascular Research Institute’s Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It reviews our current understanding of endpoints used in phase 2 and 3 trials for pulmonary hypertension and discusses in detail the value of newer approaches. These include the roles of composite endpoints and how these can be developed and validated. The newer concept of risk analysis is also discussed, including how such risk scores might be utilised as endpoints in clinical trials.

Right ventricular failure is a leading cause of mortality in patients with pulmonary arterial hypertension (PAH). However, up to 25% of such patients die unexpectedly, without warning signs of hemodynamical decompensation. We previously documented that pulmonary artery (PA) dilatation significantly increases the risk of those deaths. Some of them may be due to dissection of PA resulting in cardiac tamponade. However, direct confirmation of this mechanism is difficult as most of such deaths occur outside hospitals. We present 4 patients with severe PAH and PA dilatation in whom PA dissection has been confirmed. Three patients had IPAH, one had PAH associated with congenital heart disease. All patients had mean pulmonary artery pressure (PAP) > 50 mmHg at diagnosis and dissection occurred late in the course of apparently well controlled disease (6 to 14 years). Several clinical elements were common to our patients - high systolic PAP, long lasting PH, progressive dilatation of PA to more than 50 mm with chest pain prior to dissection. However, clinical course followed three different patterns: sudden death due to cardiac tamponade, hemopericarditis caused by blood leaking from dissected aneurysm with imminent but not immediate cardiac tamponade, or chronic asymptomatic PA dissection. Indeed, two of our patients are alive and on lung transplantation waiting list for more than 2 years now. Further research is needed to suggest optimal management strategies for patients with stable PAH but significantly dilated proximal pulmonary arteries or confirmed PA dissection depending on the clinical presentation and expected outcome.

Chronic thromboembolic pulmonary disease results from the incomplete resolution of thrombi, leading to fibrotic obstructions. These vascular obstructions and additional microvasculopathy may lead to chronic thromboembolic pulmonary hypertension (CTEPH) with increased pulmonary arterial pressure and pulmonary vascular resistance, which, if left untreated, can lead to right heart failure and death. The pathobiology of CTEPH has been challenging to unravel due to its rarity, possible interference of results with anticoagulation, difficulty in selecting the most relevant study time point in relation to presentation with acute pulmonary embolism (PE), and lack of animal models. In this article, we review the most relevant multifaceted cross-talking pathogenic mechanisms and advances in understanding the pathobiology in CTEPH, as well as its challenges and future direction. There appears to be a genetic background affecting the relevant pathological pathways. This includes genetic associations with dysfibrinogenemia resulting in fibrinolysis resistance, defective angiogenesis affecting thrombus resolution, and inflammatory mediators driving chronic inflammation in CTEPH. However, these are not necessarily specific to CTEPH and some of the pathways are also described in acute PE or deep vein thrombosis. In addition, there is a complex interplay between angiogenic and inflammatory mediators driving thrombus non-resolution, endothelial dysfunction, and vascular remodeling. Furthermore, there are data to suggest that infection, the microbiome, circulating microparticles, and the plasma metabolome are contributing to the pathobiology of CTEPH.

Acute pulmonary embolism (PE) is a disease frequently encountered in clinical practice. While the management of haemodynamically stable, low risk patients with acute PE is well established, managing intermediate disease often presents a therapeutic dilemma. In this review, we discuss the various therapeutic options available in this patient group. This includes thrombolysis, surgical embolectomy and catheter directed techniques. We have also explored the role of specialist PE response teams in the management of such patients. ​

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients (IPAH lung disease) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease (IPAH no lung disease). Patients with ‘IPAH lung disease’ have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with ‘IPAH no lung disease’. We described the outcome of the cohort of patients with ‘IPAH no lung disease’ in a previous paper. Here, we have compared incident ‘IPAH lung disease’ patients with ‘IPAH no lung disease’ patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001–2009. Compared with ‘IPAH no lung disease’ (n = 355), ‘IPAH lung disease’ patients (n = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in ‘IPAH lung disease’ and ‘IPAH no lung disease’. However, survival of ‘IPAH lung disease’ was lower than ‘IPAH no lung disease’ (one year survival: 72% compared with 93%). This survival was significantly worse in ‘IPAH lung disease’ even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. ‘IPAH lung disease’ patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with ‘IPAH no lung disease’ patients. This suggests that ‘IPAH lung disease’ are a separate phenotype and should not be lumped with ‘IPAH no lung disease’ in clinical trials of Group 1 pulmonary arterial hypertension.

Pulmonary endarterectomy (PEA) may not achieve full clearance of vascular obstructions in patients with more distal chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) may be indicated to treat these residual vascular lesions. We compared whether patients post‐PEA (PP) treated by BPA derived similar benefit to those who had inoperable CTEPH (IC), and assessed predictors of BPA response after surgery. We treated 109 patients with BPA—89 with IC and 20 PP. Serial right heart catheterization performed at baseline (immediately before BPA) and 3 months after completing BPA, compared pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP) as well as change in WHO functional class and 6‐minute walk distance. We also assessed the impact of total thrombus tail length (TTTL) from photographed PEA surgical specimens and PP computed tomography pulmonary angiography (CTPA)‐quantified residual disease burden on BPA response. PP and IC groups did not differ significantly in terms of demographics, baseline hemodynamics or procedural characteristics. However, IC derived greater hemodynamic benefit from BPA: ΔPVR (−27.9 ± 20.2% vs. −13.9 ± 23.9%, p  < 0.05) and ΔmPAP (−17.1 ± 14.4% vs. −8.5 ± 18.0%, p  < 0.05). There was a negative correlation between pre‐BPA PVR and TTTL ( r  = −0.47, p  < 0.05) which persisted post‐BPA. PVR, mPAP, WHO FC and 6MWD were not improved significantly post‐BPA in PP patients. BPA response was not related to TTTL terciles or CTPA‐quantified residual disease burden. Patients PP experienced inferior response to BPA, despite similar baseline and procedural characteristics to IC. BPA does not abolish the relationship between TTTL and postsurgical PVR in PP patients, suggesting that BPA is less effective in treating residual PH after surgery in an experienced surgical center.