Neil Hamilton

Aspire Registry: assessing the spectrum of pulmonary hypertension identified at a referral centre

Pulmonary hypertension (PH) is a heterogeneous condition. To date, no registry data exists reflecting the spectrum of disease across the five diagnostic groups encountered in a specialist referral centre. Data was retrieved for consecutive, treatment-naïve cases diagnosed between 2001 and 2010 using a catheter-based approach. 1,344 patients were enrolled, with a mean follow-up of 2.9 yrs. The 3-yr survival was 68% for pulmonary arterial hypertension (PAH), 73% for PH associated with left heart disease, 44% for PH associated with lung disease (PH-lung), 71% for chronic thromboembolic PH (CTEPH) and 59% for miscellaneous PH. Compared with PAH, survival was inferior in PH-lung and superior in CTEPH (p<0.05). Multivariate analysis demonstrated that diagnostic group independently predicted survival. Within PAH, Eisenmenger’s survival was superior to idiopathic PAH, which was superior to PAH associated with systemic sclerosis (p<0.005). Within PH-lung, 3-yr survival in sleep disorders/alveolar hypoventilation (90%) was superior to PH-lung with chronic obstructive pulmonary disease (41%) and interstitial lung disease (16%) (p<0.05). In CTEPH, long-term survival was best in patients with surgically accessible disease undergoing pulmonary endarterectomy. In this large registry of consecutive, treatment-naïve patients identified at a specialist PH centre, outcomes and characteristics differed between and within PH groups. The current system of classification of PH has prognostic value even when adjusted for age and disease severity, emphasising the importance of systematic evaluation and precise classification.

Pulmonary hypertension in COPD: results from the ASPIRE registry

The phenotype and outcome of severe pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is described in small numbers, and predictors of survival are unknown. Data was retrieved for 101 consecutive, treatment-naïve cases of pulmonary hypertension in COPD. Mean±sd follow-up was 2.3±1.9 years. 59 patients with COPD and severe pulmonary hypertension, defined by catheter mean pulmonary artery pressure ≥40 mmHg, had significantly lower carbon monoxide diffusion, less severe airflow obstruction but not significantly different emphysema scores on computed tomography compared to 42 patients with mild–moderate pulmonary hypertension. 1- and 3-year survival for severe pulmonary hypertension, at 70% and 33%, respectively, was inferior to 83% and 55%, respectively, for mild–moderate pulmonary hypertension. Mixed venous oxygen saturation, carbon monoxide diffusion, World Health Organization functional class and age, but not severity of airflow obstruction, were independent predictors of outcome. Compassionate treatment with targeted therapies in 43 patients with severe pulmonary hypertension was not associated with a survival benefit, although improvement in functional class and/or fall in pulmonary vascular resistance >20% following treatment identified patients with improved survival. Standard prognostic markers in COPD have limited value in patients with pulmonary hypertension. This study identifies variables that predict outcome in this phenotype. Despite poor prognosis, our data suggest that further evaluation of targeted therapies is warranted.

Magnetic Resonance Imaging in the Prognostic Evaluation of Patients with Pulmonary Arterial Hypertension

&NA; Rationale: Prognostication is important when counseling patients and defining treatment strategies in pulmonary arterial hypertension (PAH). Objectives: To determine the value of magnetic resonance imaging (MRI) metrics for prediction of mortality in PAH. Methods: Consecutive patients with PAH undergoing MRI were identified from the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) pulmonary hypertension registry. Measurements and Main Results: During the follow‐up period of 42 (range, 17‐142) months 576 patients were studied and 221 (38%) died. A derivation cohort (n = 288; 115 deaths) and validation cohort (n = 288; 106 deaths) were identified. We used multivariate Cox regression and found two independent MRI predictors of death (P < 0.01): right ventricular end‐systolic volume index adjusted for age and sex, and the relative area change of the pulmonary artery. A model of MRI and clinical data constructed from the derivation cohort predicted mortality in the validation cohort at 1 year (sensitivity, 70 [95% confidence interval (CI), 53‐83]; specificity, 62 [95% CI, 62‐68]; positive predictive value [PPV], 24 [95% CI, 16‐32]; negative predictive value [NPV], 92 [95% CI, 87‐96]) and at 3 years (sensitivity, 77 [95% CI, 67‐85]; specificity, 73 [95% CI, 66‐85]; PPV, 56 [95% CI, 47‐65]; and NPV, 87 [95% CI, 81‐92]). The model was more accurate in patients with idiopathic PAH at 3 years (sensitivity, 89 [95% CI, 65‐84]; specificity, 76 [95% CI, 65‐84]; PPV, 60 [95% CI, 46‐74]; and NPV, 94 [95% CI, 85‐98]). Conclusions: MRI measurements reflecting right ventricular structure and stiffness of the proximal pulmonary vasculature are independent predictors of outcome in PAH. In combination with clinical data MRI has moderate prognostic accuracy in the evaluation of patients with PAH.

Ambrisentan therapy in pulmonary hypertension: clinical use and tolerability in a referral centre

Introduction: Ambrisentan is an oral selective endothelin receptor antagonist licensed for use in pulmonary arterial hypertension (PAH). There are few data on clinical use and long-term tolerability in a wider range of patients with pulmonary hypertension (PH). Methods: All patients treated with ambrisentan over a 4-year period were identified. Baseline characteristics, liver function test (LFT) results and World Health Organization (WHO) functional class were retrieved from hospital databases. Results: 272 patients received ambrisentan between March 2009 and June 2013 (32% idiopathic PAH, 36% connective tissue disease PAH, 11% congenital heart disease PAH, 6% portopulmonary hypertension, 1% HIV PAH, 4% PH in association with lung disease, 8% chronic thromboembolic PH and 2% PH in association with sarcoidosis). 33.5% of patients received ambrisentan as monotherapy and 12% received ambrisentan as their initial PH therapy. 18% stopped treatment due to side effects and 12% stopped due to lack of efficacy. Oedema was the most common side effect leading to cessation of therapy, which occurred in 7% of patients. 57% of patients who discontinued ambrisentan due to side effects also discontinued other PAH therapies due to side effects previously or subsequently. Ambrisentan was discontinued in two (<1%) patients due to abnormal LFTs. The 3-year survival in congenital heart disease PAH, idiopathic PAH and systemic sclerosis-associated PAH was 80%, 62%, and 38%, respectively (p = 0.003). Survival was superior in patients in whom WHO functional class improved in response to therapy. Conclusion: Ambrisentan is used as an initial therapy and as monotherapy in a minority of patients in a large UK PH referral centre. Discontinuation due to side effects, and especially oedema, was higher than reported in previous studies while discontinuation due to abnormal LFTs was very uncommon. A majority of patients who discontinued therapy due to side effects also previously or subsequently discontinued other PAH therapies. Improvement in WHO functional class was associated with superior survival.

Bosutinib therapy resulting in severe deterioration of pre-existing pulmonary arterial hypertension.

We read with interest the recent correspondence from Quilot et al. [1] describing a likely case of ponatinib-associated pulmonary arterial hypertension (PAH). The authors hypothesised that the mechanism by which tyrosine kinase inhibitors (TKIs) such as dasatinib and ponatinib, used for the treatment of chronic myeloid leukaemia (CML), induce PAH may involve their common inhibition of the non-receptor tyrosine kinase, Src [1]. Here, we present a patient who developed marked worsening of pre-existing TKI-associated PAH following commencement of bosutinib, a third-generation TKI also known to inhibit Src [2]. After marked improvement on withdrawal of bosutinib, the patient experienced further significant worsening of PAH after commencing ponatinib. We believe this is the first reported case linking bosutinib with PAH. It also supports the association between ponatinib and PAH and represents the first time that the development or worsening of PAH associated with multiple TKIs in the same patient has been reported. A patient with severe worsening of pre-existing PAH following treatment with bosutinib improved on cessation http://ow.ly/gJy7302uXL7

Incremental shuttle walk test distance and autonomic dysfunction predict survival in pulmonary arterial hypertension

BACKGROUND To ensure effective monitoring of pulmonary arterial hypertension (PAH), a simple, reliable assessment of exercise capacity applicable over a range of disease severity is needed. The aim of this study was to assess the ability of the incremental shuttle walk test (ISWT) to correlate with disease severity, measure sensitivity to change, and predict survival in PAH. METHODS We enrolled 418 treatment-naïve patients with PAH with baseline ISWT within 3 months of cardiac catheterization. Clinical validity and prognostic value of ISWT distance were assessed at baseline and 1 year. RESULTS ISWT distance was found to correlate at baseline with World Health Organization functional class, Borg score, and hemodynamics without a ceiling effect (all p < 0.001). Walking distance at baseline and after treatment predicted survival; the area under the receiver operating characteristic curve for ability of ISWT distance to predict mortality was 0.655 (95% confidence interval 0.553-0.757; p = 0.004) at baseline and 0.737 (95% confidence interval 0.643-0.827; p < 0.001) at 1 year after initiation of treatment. Change in ISWT distance also predicted survival (p = 0.04). Heart rate (HR) and systolic blood pressure (SBP) parameters reflecting autonomic response to exercise (highest HR, change in HR, HR recovery at 1 minute >18 beats/min, highest SBP, change in SBP, and 3-minute SBP ratio) were significant predictors of survival (all p < 0.05). CONCLUSIONS In patients with PAH, the ISWT is simple to perform, allows assessment of maximal exercise capacity, is sensitive to treatment effect, predicts outcome, and has no ceiling effect. Also, measures of autonomic function made post-exercise predict survival in PAH.

Long-term outcomes of domiciliary intravenous iloprost in idiopathic and connective tissue disease-associated pulmonary arterial hypertension

There are few published data on the efficacy of i.v. iloprost in pulmonary arterial hypertension (PAH). We present long‐term outcomes in PAH patients receiving i.v. iloprost in a large UK referral centre.

The impact of patient choice on survival in chronic thromboembolic pulmonary hypertension

Pulmonary endarterectomy (PEA) is the gold standard treatment for operable chronic thromboembolic pulmonary hypertension (CTEPH). However, a proportion of patients with operable disease decline surgery. There are currently no published data on this patient group. The aim of this study was to identify outcomes and prognostic factors in a large cohort of consecutive patients with CTEPH. Data were collected for consecutive, treatment-naive CTEPH patients at the Pulmonary Vascular Disease Unit of the Royal Hallamshire Hospital (Sheffield, UK) between 2001 and 2014. Of 550 CTEPH patients (mean±sd age 63±15 years, follow-up 4±3 years), 49% underwent surgery, 32% had technically operable disease and did not undergo surgery (including patient choice n=72 and unfit for surgery n=63), and 19% had inoperable disease due to disease distribution. The 5-year survival was superior in patients undergoing PEA (83%) versus technically operable disease who did not undergo surgery (53%) and inoperable due to disease distribution (59%) (p<0.001). Survival was superior in patients following PEA compared with those offered but declining surgery (55%) (p<0.001). In patients offered PEA, independent prognostic factors included mixed venous oxygen saturation, gas transfer and patient decision to proceed to surgery. Outcomes in CTEPH following PEA are excellent and superior to patients declining surgery, and strongly favour consideration of a surgical intervention in eligible patients. Outcomes for patients undergoing pulmonary endarterectomy are excellent and superior to patients declining surgery http://ow.ly/9UZw30kA28m

P28 Chronic thromboembolic pulmonary hypertension: long term outcomes in surgical and non-surgical patients

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is commonly associated with a history of venous thromboembolism. Pulmonary endarterectomy (PEA) offers a potential cure in surgically accessible disease. However, a significant proportion of patients with CTEPH may not undergo surgery due to various reasons including disease distribution, comorbidities and patient choice This group of patients have previously been considered to have a poor outcome although an international registry has recently reported on improved medium term outcomes in this patient population. Aims and objectives To compare long term survival of patients with CTEPH undergoing pulmonary endarterectomy (CTEPH-surgical-operated), surgically accessible disease not undergoing pulmonary endarterectomy (CTEPH-surgical-not-operated), surgically inaccessible disease (CTEPH-non-surgical). Methods Data was retrieved from hospital records and departmental database for consecutive, treatment-naïve patients with CTEPH diagnosed between 1st January 2001 and 30th November 2014 and followed up till 30th November 2015 at the Sheffield Pulmonary Vascular Disease Unit and collected in the ASPIRE registry. Patients with suspected CTEPH undergo systematic evaluation but formal pulmonary angiography is only performed when other imaging modalities such as CTPA, MR imaging and nuclear medicine imaging are non-diagnostic. Results 592 patients, mean age (± standard deviation), 65 ± 22 years, mean pulmonary arterial pressure 48 ± 13 mmHg and median pulmonary vascular resistance 480 ± 463 dynes/sec/cm-5 were identified and followed for 4.3 ± 3.2 years. 5 year survival was significantly (p < 0.001) better in CTEPH-surgical-operated (n = 279) at 82.9 ± 3.1% compared to CTEPH-surgical-not-operated (n = 206) at 44.4 ± 5% (66.7 ± 9.1% patient choice, 39.4 ± 6% comorbidities) and 53.4 ± 5.8% in CTEPH-non-surgical (n = 107). Only 4% of the patients in our study were investigated with conventional pulmonary angiography.The median time to PEA surgery from diagnosis was 10.2 months and did not affect long term survival (p = 0.52). Conclusions For operable patients with CTEPH pulmonary endarterectomy is associated with an excellent long term outcome, the long-term survival of patients with surgical disease who decline surgery is significantly better than historically reported and that a non-invasive multimodality imaging approach can be used to assess patients with suspected CTEPH. Furthermore there is no time from diagnosis to surgery which predicts outcome. Abstract P28 Figure 1 Kaplan-Meier estimates survival from date of diagnosis in CTEPH, surgical, operated, CTEPH, surgical, not-operated and CTEPH, non-surgical patients,log-rank test, p < 0.001

Diagnosis of Pulmonary Hypertension with Cardiac MRI: Derivation and Validation of Regression Models

Purpose To derive and test multiparametric cardiac MRI models for the diagnosis of pulmonary hypertension (PH). Materials and Methods Images and patient data from consecutive patients suspected of having PH who underwent cardiac MRI and right-sided heart catheterization (RHC) between 2012 and 2016 were retrospectively reviewed. Of 2437 MR images identified, 603 fit the inclusion criteria. The mean patient age was 61 years (range, 18–88 years; mean age of women, 60 years [range, 18–84 years]; mean age of men, 62 years [range, 22–88 years]). In the first 300 patients (derivation cohort), cardiac MRI metrics that showed correlation with mean pulmonary arterial pressure (mPAP) were used to create a regression algorithm. The performance of the model was assessed in the 303-patient validation cohort by using receiver operating characteristic (ROC) and χ2 analysis. Results In the derivation cohort, cardiac MRI mPAP model 1 (right ventricle and black blood) was defined as follows: −179 + loge interventricular septal angle × 42.7 + log10 ventricular mass index (right ventricular mass/left ventricular mass) × 7.57 + black blood slow flow score × 3.39. In the validation cohort, cardiac MRI mPAP model 1 had strong agreement with RHC-measured mPAP, an intraclass coefficient of 0.78, and high diagnostic accuracy (area under the ROC curve = 0.95; 95% confidence interval [CI]: 0.93, 0.98). The threshold of at least 25 mm Hg had a sensitivity of 93% (95% CI: 89%, 96%), specificity of 79% (95% CI: 65%, 89%), positive predictive value of 96% (95% CI: 93%, 98%), and negative predictive value of 67% (95% CI: 53%, 78%) in the validation cohort. A second model, cardiac MRI mPAP model 2 (right ventricle pulmonary artery), which excludes the black blood flow score, had equivalent diagnostic accuracy (ROC difference: P = .24). Conclusion Multiparametric cardiac MRI models have high diagnostic accuracy in patients suspected of having pulmonary hypertension. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Colletti in this issue.