Impact of Left Heart Disease Risk Factors on Outcomes in Pulmonary Arterial Hypertension Therapy.

BACKGROUND: Current guidelines recommend initial monotherapy for pulmonary arterial hypertension (PAH) with cardiopulmonary comorbidities, despite limited available evidence to guide management. RESEARCH QUESTION: Do left heart disease (LHD) risk factors have an impact on treatment response and influence applicability of risk assessment in a real-world cohort of patients with PAH? STUDY DESIGN AND METHODS: The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial criteria was used to define the phenotype of patients with PAH with risk factors for LHD. Treatment strategy, functional outcome, long-term survival, and risk discrimination were compared with a reference PAH cohort using the Pulmonary Hypertension Society of Australia and New Zealand Registry. RESULTS: A total of 487 incident patients with PAH diagnosed between 2011 and 2020 were included. Of these, 103 (21.1%) fulfilled the definition of PAH with LHD risk factors, with 384 (78.9%) remaining as the reference group. Patients in the PAH with LHD risk factors group were older (66 ± 13 vs 58 ± 19 years; P < .001), had lower pulmonary vascular resistance (393 ± 266 vs 708 ± 391 dyn.s/cm5; P = .031), and had worse 6-min walk distance (286 ± 130 vs 327 ± 136 m; P = .005) at diagnosis. The PAH with LHD risk factors group was less likely to receive initial combination therapy (27% vs 44%; P = .02). Changes in 6-min walk distance at 12 months were similar in both groups (43 ± 77 m in the PAH with LHD risk factors group and 50 ± 90 m in the reference group; P = .50), including when stratified by initial treatment strategy (PAH with LHD risk factors group vs reference PAH group: monotherapy: 40 ± 81 vs 38 ± 95 m, P = .87; combination therapy: 53 ± 78 vs 64 ± 106 m, P = .511). Functional class improvements were also similar in both groups. REVEAL Registry 2.0 risk score effectively discriminated risk in both populations (C statistic = 0.756 for the PAH with LHD risk factors group and C statistic = 0.750 for the reference PAH group). There was no difference in survival between the two groups (log-rank test, P = .29). INTERPRETATION: In a real-world cohort, patients with PAH with LHD risk factors were less likely to be exposed to initial combination therapy. Nevertheless, selected patients with PAH with LHD risk factors who were treated with initial combination therapy derived similar functional response compared with the reference group. Further studies are needed to phenotype patients with PAH with cardiopulmonary comorbidities who may benefit from initial combination therapy.

Acute Vasoreactivity Testing and Outcomes in Pulmonary Arterial Hypertension: A Call for Increased Testing.

BACKGROUND: Pulmonary arterial hypertension (PAH) has a progressive, unremitting clinical course. Vasoreactivity testing (VdT) during right heart catheterisation (RHC) identifies a subgroup with excellent long-term response to calcium channel blockade (CCB). Reporting on these patients is limited. Established in 2011, the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry offers the opportunity to assess the frequency of VdT during RHC, treatment and follow up of PAH patients. METHODS: Registry data from 3,972 PAH patients with index RHC revealed 1,194 VdT appropriate patients. Data was analysed in three groups: 1) VdT+CCB+: VdT positive, CCB treated; 2) VdT+CCB-: VdT positive, no CCB prescribed, 3) VdT-/noVdT: VdT negative, or VdT not tested. Data was reviewed for adherence to guidelines, clinical response (World Health Organization functional class [WHO FC], 6-minute-walk-distance [6MWD], RHC), and outcomes (survival or lung transplantation). RESULTS: Patients included had idiopathic (IPAH=1,087), heritable (HPAH=67) and drug or toxin-induced PAH (DPAH=40). A VdT was performed in 22% (268/1,194), with incomplete data in 26% (70/268); 28% (55/198) were VdT+. Analysis group allocation was: VdT+CCB+ (33/55), VdT+CCB- (22/55), VdT- (143)/noVdT (996). From patients with 1-year data VdT+CCB+ and VdT-/noVdT patients improved WHO FC, 6MWD and cardiac index (CI); VdT+CCB- data remained similar. Within the VdT+CCB+ group, 30% (10/33) were long-term CCB responders with a 100% 5-year survival; non-responders had a 61% survival at 5.4 years. Long-term responders were younger at diagnosis (40 yrs vs 54 yrs). CONCLUSION: Use of VdT testing and documentation is poor in this contemporary patient cohort. Nonetheless, survival in VdT+CCB+ patients from the PHSANZ registry is excellent, supporting guidelines promoting VdT testing. Strategies to promote the use of VdT are warranted.

Chronic thromboembolic pulmonary hypertension in Australia and New Zealand: An analysis of the PHSANZ registry.

BACKGROUND AND OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious condition occurring in 2%-4% of patients after acute pulmonary embolism. Pulmonary endarterectomy (PEA) is a potential cure for technically operable disease. The epidemiology and long-term outcomes of CTEPH have not been previously described in Australia and New Zealand. METHODS: Data were extracted from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) registry for patients diagnosed with CTEPH between January 2004 and March 2020. Baseline characteristics, treatment strategies, outcome data and long-term survival are reported. RESULTS: A total of 386 patients were included with 146 (37.8%) undergoing PEA and 240 (62.2%) in the non-PEA group. PEA patients were younger (55 ± 16 vs. 62 ± 16 years, p < 0.001) with higher baseline 6-min walk distance (6MWD; 405 ± 122 vs. 323 ± 146 m, p = 0.021), whilst both groups had similar baseline pulmonary haemodynamics. Pulmonary hypertension-specific therapy was used in 54% of patients post-PEA and 88% in the non-PEA group. The 1-, 3- and 5-year survival rates were 93%, 87% and 84% for the PEA group compared to 86%, 73% and 62%, respectively, for the non-PEA group (p < 0.001). Multivariate survival analysis showed baseline 6MWD was an independent predictor of survival in both operated and medically managed patients. CONCLUSION: In this first multicentre report of CTEPH in Australia and New Zealand, long-term survival is comparable to that in other contemporary CTEPH registries. However, PEA was only performed in a minority of CTEPH patients (37.8%) and significantly less than overseas reports. Greater awareness of PEA and improved patient access to experienced CTEPH centres are important priorities.

Use of eHealth in the management of pulmonary arterial hypertension: review of the literature.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe chronic condition associated with poor quality of life and high risks of mortality and hospitalisation. The utilisation of novel diagnostic technologies has improved survival rates although the effectiveness of Electronic Health (eHealth) interventions in patients with a chronic cardiopulmonary disease remains controversial. As the effectiveness of eHealth can be established by specific evaluation for different chronic health conditions, the aim of this study was to explore and summarise the utilisation of eHealth in PAH. METHOD: We searched PubMed, CINAHL and Embase for all studies reporting clinical trials on eHealth solutions for the management of PAH. No limitations in terms of study design or date of publication were imposed. RESULTS: 18 studies (6 peer-reviewed journal papers and 12 conference papers) were identified. Seven studies addressed the accuracy, safety or reliability of eHealth technologies such as intra-arterial haemodynamic monitoring of the pulmonary artery pressure, self-administered 6-Minute walk test App, computerised step-pulse oximeter and ambulatory impedance cardiography. Two studies evaluated eHealth as part of the medical management and showed a reduction in hospitalisation rate. CONCLUSIONS: The evidence of eHealth supporting the management of people with PAH is limited and only embraced through a few studies of small sample size and short-term duration. Given the proposed clinical benefits in heart failure, we postulate that the evaluation of eHealth for the clinical management of PAH is highly warranted.

Successful treatment of telomeropathy-related interstitial lung disease with immunosuppression and danazol.

We report the case of a 42-year-old female with a history of finger clubbing which improved during pregnancy, a history of unexplained hepatosplenomegaly, and subsequent non-specific interstitial pneumonia with respiratory failure. Given a personal and family history of early greying of the hair, the peripheral blood monocyte telomere length was measured and was confirmed to be <1st centile, explaining the multiorgan presentation. She was treated with prednisolone, mycophenolate mofetil, and the synthetic androgen danazol with a dramatic improvement in respiratory failure and lung function. After 18 months of danazol treatment, the peripheral blood monocyte telomere length had returned to the normal range.

Pulmonary arterial hypertension with below threshold pulmonary vascular resistance.

Pulmonary vascular resistance (PVR) >3 Wood units is a criterion of the haemodynamic definition of pulmonary arterial hypertension (PAH). However, this cut-off is conservative and arbitrarily defined. Data is lacking on the natural history, response to therapy and survival of patients diagnosed with precapillary pulmonary hypertension (PH) with mild or borderline elevation of PVR.In Australia, PAH therapy could be prescribed solely on mean pulmonary arterial pressure (PAP) and pulmonary arterial wedge pressure (PAWP) criteria. Using the Australian and New Zealand Pulmonary Hypertension Registry, we aimed to study a population diagnosed with PAH between January 2004 and December 2017 with the pre-defined haemodynamic characteristics of mean PAP ≥25 mmHg, PAWP ≤15 mmHg and PVR <3 Wood units.Eighty-two patients met the pre-defined haemodynamic inclusion criteria (mean age 63±11 years; 67 females). Underlying aetiologies included idiopathic disease (n=39), connective tissue disease (CTD; n=42) and HIV infection (n=1). At diagnosis, mean PAP was 27 mmHg (interquartile range (IQR) 25-30 mmHg), PAWP 13 mmHg (IQR 11-14 mmHg) and PVR 2.2 Wood units (IQR 1.9-2.7 Wood units). Baseline 6-min walk distance (6MWD) was 352 m (IQR 280-416 m) and 77% of subjects were in New York Heart Association (NYHA) functional class 3 or 4. All patients were commenced on initial monotherapy with an endothelin receptor antagonist (ERA; n=66) or phosphodiesterase type-5 inhibitor (PDE5i; n=16). At first re-evaluation, 6MWD increased by 46 m (IQR 7-96 m) and 35% of subjects demonstrated improvement in NYHA functional class. After a median follow-up of 65 months (IQR 32-101 months), 18 out of 82 subjects (22.0%) had died, with estimated 1-year and 5-year survival rates of 98% and 84%, respectively. Death attributed to PAH occurred in six out of these 18 patients (33.3%, 7% of total cohort).Patients with precapillary PH and "borderline" PVR falling outside the current definition have adverse outcomes. Such patients appear to respond to PAH therapy; however, this requires further study in randomised trials.

Pharmacological Treatment of Pulmonary Arterial Hypertension in Australia: Current Trends and Challenges.

BACKGROUND: Combination drug therapy for pulmonary arterial hypertension (PAH) is the international standard of care for most patients, however in Australia there are barriers to drug access. This study evaluates current treatment of PAH patients in Australia and the consistency of therapy with international guidelines. METHODS: Cross-sectional analysis of patients with Group 1 PAH enrolled in the Pulmonary Hypertension Society of Australia and New Zealand Registry (PHSANZ) at 31 December 2017. Drug treatment was classified as monotherapy or combination therapy and adequacy of treatment was determined by risk status assessment using the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk calculator. Predictors of monotherapy were assessed using a generalised linear model with Poisson distribution and logarithmic link function. RESULTS: 1,046 patients met the criteria for analysis. Treatment was classified as monotherapy in 536 (51%) and combination therapy in 510 (49%) cases. Based on REVEAL 2.0, 184 (34%) patients on monotherapy failed to meet low-risk criteria and should be considered inadequately treated. Independent predictors of monotherapy included age greater than 60 years (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.09-1.38; p=0.001), prevalent enrolment in the registry (RR 1.21 [95%CI 1.08-1.36]; p=0.001) and comorbid systemic hypertension (RR 1.17 [95%CI 1.03-1.32]; p=0.014), while idiopathic/heritable/drug-induced PAH subtype (RR 0.85 [95%CI 0.76-0.96]; p=0.006), functional class IV (RR 0.50 [95%CI 0.29-0.86]; p=0.012), increased right ventricular systolic pressure (RR 0.99 [95%CI 0.99-1.00]; p<0.001) and increased pulmonary vascular resistance (RR 0.96 [95%CI 0.95-0.98]; p<0.001) were less likely to be associated with monotherapy. CONCLUSIONS: Most Australian PAH patients are treated with monotherapy and a significant proportion remain at risk of poor outcomes. This is below the standard of care recommended by international guidelines and at risk patients should be escalated to combination therapy.

Diagnostic delay in pulmonary arterial hypertension: Insights from the Australian and New Zealand pulmonary hypertension registry.

BACKGROUND AND OBJECTIVE: Early diagnosis of PAH is clinically challenging. Patterns of diagnostic delay in Australian and New Zealand PAH populations have not been explored in large-scale studies. We aimed to evaluate the magnitude, risk factors and survival impact of diagnostic delay in Australian and New Zealand PAH patients. METHODS: A cohort study of PAH patients from the PHSANZ Registry diagnosed from 2004 to 2017 was performed. Diagnostic interval was the time from symptom onset to diagnostic right heart catheterization as recorded in the registry. Factors associated with diagnostic delay were analysed in a multivariate logistic regression model. Survival rates were compared across patients based on the time to diagnosis using Kaplan-Meier method and Cox regression. RESULTS: A total of 2044 patients were included in analysis. At diagnosis, median age was 58 years (IQR: 43-69), female-to-male ratio was 2.8:1 and majority of patients were in NYHA FC III-IV (82%). Median diagnostic interval was 1.2 years (IQR: 0.6-2.7). Age, CHD-PAH, obstructive sleep apnoea and peripheral vascular disease were independently associated with diagnostic interval of ≥1 year. No improvement in diagnostic interval was seen during the study period. Longer diagnostic interval was associated with decreased 5-year survival. CONCLUSION: PAH patients experience significant diagnostic interval, which has not improved despite increased community awareness. Age, cardiovascular and respiratory comorbidities are significantly associated with longer time to diagnosis. Mortality rates appear higher in patients who experience longer diagnostic interval.

Effectiveness of epoprostenol in the management of pulmonary arterial hypertension: findings of an Australian retrospective chart review.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressively fatal disease. Parenteral prostanoids, including intravenous (IV) epoprostenol, are the most effective therapies for PAH. As epoprostenol requires continuous infusion, therapy is challenging and use is managed by specialist units. AIMS: To describe the clinical outcomes for the use of IV epoprostenol in an Australian pulmonary vascular disease unit and identify opportunities to improve its use. METHOD: We conducted a retrospective chart review of all adult patients who received IV epoprostenol for PAH at Prince Charles Hospital. Data were collected at baseline, initiation of epoprostenol and quarterly to the end of the audit period or the discontinuation of epoprostenol. Descriptive statistics were performed and comparisons made to epoprostenol initiation. Kaplan-Meier curves were used to estimate survival outcomes. RESULTS: Thirty-nine patients received epoprostenol therapy. Most (87.2%) were female, had connective tissue disease (46.2%) or idiopathic PAH (35.9%) and had a World Health Organization functional Class of III or IV at initiation. The mean duration of epoprostenol therapy was 2.9 years. Intravenous epoprostenol was associated with favourable outcomes; 1, 3 and 5-year survival rates since initiation of 90.0, 75.8 and 68.2%; robust improvements in functional class; and improvements in 6-min walking distance of 160.4 m at 3 years; 94.9% patients experienced at least one drug-related adverse event and line complications were common. CONCLUSION: Epoprostenol therapy was associated with impressive survival rates and durable improvements in functional outcomes. Epoprostenol therapy is challenging; however, it is manageable by the majority of patients with most experiencing positive, sustainable outcomes.

Retrospective Validation of the REVEAL 2.0 Risk Score With the Australian and New Zealand Pulmonary Hypertension Registry Cohort.

BACKGROUND: Pulmonary arterial hypertension (PAH) prognosis has improved with targeted therapies; however, the long-term outlook remains poor. Objective multiparametric risk assessment is recommended to identify patients at risk of early morbidity and mortality, and for optimization of treatment. The US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk score is a new model proposed for the follow-up of patients with PAH but has not been externally validated. METHODS: The REVEAL 2.0 risk score was applied to a mixed prevalent and incident cohort of patients with PAH (n = 1,011) from the Pulmonary Hypertension Society of Australia and New Zealand (PHSANZ) Registry. Kaplan-Meier survival was estimated for each REVEAL 2.0 risk score strata and for a simplified three-category (low, intermediate, and high risk) model. Sensitivity analysis was performed on an incident-only cohort. RESULTS: The REVEAL 2.0 model effectively discriminated risk in the large external PHSANZ Registry cohort, with a C statistic of 0.74 (both for full eight-tier and three-category models). When applied to incident cases only, the C statistic was 0.73. The three-category REVEAL 2.0 model demonstrated robust separation of 12- and 60-month survival estimates (all risk category comparisons P < .001). Although the full eight-tier REVEAL 2.0 model separated patients at low, intermediate, and high risk, survival estimates overlapped within some of the intermediate- and high-risk strata. CONCLUSIONS: The REVEAL 2.0 risk score was validated in a large external cohort from the PHSANZ Registry. The REVEAL 2.0 model can be applied for risk assessment of patients with PAH at follow-up. The simplified three-category model may be preferred for clinical use and for future comparison with other prognostic models.

Study protocol for a randomised controlled trial of exercise training in pulmonary hypertension (ExTra_PH).

BACKGROUND: Exercise training is an integral component of evidence-based management programs for many chronic cardiac and respiratory conditions. Despite this, there are limited high-quality studies available on the significance of exercise training in pulmonary hypertension (PH). The aim of this study is to evaluate the short and long-term effectiveness of exercise training in PH patients in terms of exercise capacity, quality of life, cardiac function and disease progression. METHODS: This randomized control trial will aim to recruit 50 medically stable PH patients categorised as New York Heart Association functional classification II-III. Participants will be randomly allocated to either the supervised exercise training group or usual care group for the 8-week study period. Exercise training will be conducted in an outpatient setting. Measurements at baseline and following the 8-week study period include exercise capacity (6 min walk distance and cardiopulmonary exercise test), cardiac function (exercise cardiac magnetic resonance imaging [CMRI] and echocardiography), health-related quality of life (Cambridge Pulmonary Hypertension Outcome Review), adverse responses to exercise training and time to clinical worsening. In addition, participants will be followed up for a minimum of 2 year period from commencement of the study so as to monitor long-term clinical outcomes i.e. time to clinical worsening. DISCUSSION: This study will determine whether an 8-week outpatient based supervised exercise training program is safe and beneficial for medically stable PH patients in the short and long term. This will be the first study to examine the impact of exercise training on right heart function using exercise CMRI. Results from the study will contribute new knowledge in relation to the impact of exercise training on cardiac function, long-term prognosis and inform clinical practice guidelines for this patient population. Moreover, the study will add to our understanding regarding the efficacy of exercise training in individuals with PH in an outpatient setting. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: ACTRN12616001467426 . Registered 21st October, 2016.

Survival of Idiopathic Pulmonary Arterial Hypertension Patients in the Modern Era in Australia and New Zealand.

BACKGROUND: Epidemiology and treatment strategies continue to evolve in pulmonary arterial hypertension (PAH). We sought to define the characteristics and survival of patients with idiopathic, heritable and drug-induced PAH in the current management era. METHODS: Consecutive cases of idiopathic, heritable and drug-induced PAH were prospectively enrolled into an Australian and New Zealand Registry. RESULTS: Between January 2012 and December 2016, a total of 220 incident cases were enrolled (mean age 57.2±18.7years, female 69.5%) and followed for a median duration of 26 months (IQR17-39). Co-morbidities were common such as obesity (34.1%), systemic hypertension (30.5%), coronary artery disease (16.4%) and diabetes mellitus (19.5%). Initial combination therapy was used in 54 patients (dual, n=50; triple, n=4). Estimated survival rates at 1-year, 2-years and 3-years were 95.6% (CI 92.8-98.5%), 87.3% (CI 82.5-92.4%) and 77.0% (CI 70.3-84.3%), respectively. Multivariate analysis showed that male sex and lower 6-minute distance at diagnosis independently predicted worse survival, whereas obesity was associated with improved survival. Co-morbidities other than obesity did not impact survival. Initial dual oral combination therapy was associated with a trend towards better survival compared with initial oral monotherapy (adjusted HR=0.27, CI 0.06-1.18, p=0.082) CONCLUSIONS: The epidemiology and survival of patients with idiopathic PAH in Australia and New Zealand are similar to contemporary registries reported in Europe and North America. Male sex and poorer exercise capacity are predictive of mortality whereas obesity appears to exert a protective effect. Despite current therapies, PAH remains a life-threatening disease associated with significant early mortality.

ePLAR - The echocardiographic Pulmonary to Left Atrial Ratio - A novel non-invasive parameter to differentiate pre-capillary and post-capillary pulmonary hypertension.

BACKGROUND: Right heart catheterisation is the gold-standard for differentiating pre-capillary pulmonary hypertension (high mean pulmonary artery pressure, normal pulmonary wedge pressure) from post-capillary physiology (elevated pulmonary wedge pressure). The new non-invasive parameter, ePLAR (echocardiographic Pulmonary to Left Atrial Ratio) is calculated from the maximum tricuspid regurgitation continuous wave Doppler velocity (m/s) divided by the transmitral E-wave:septal mitral annular Doppler Tissue Imaging e'-wave ratio (TRVmax/E:e'). METHODS: Pulmonary hypertension patients (mean pulmonary artery pressure>25mmHg, n=133, 66 male, average 65.0±16.8years) were classified by right heart catheterisation as pre-capillary or post-capillary [subdivided into isolated post-capillary (diastolic pulmonary gradient <7mmHg) or combined pre- and post-capillary cases]. The ePLAR values of these groups were compared to each other and to a population sample of 16,356 population reference echocardiograms. RESULTS: ePLAR values for the normal reference population of 16,356 echocardiograms (age 56±16.6years) were 0.30±0.09m/s. Pre-capillary pulmonary hypertension patients (n=35, 26 male, PAPsys 63.9±16.6mmHg, PAPdiast 24.1±7.3mmHg, PAPmean 37.9±9.4mmHg, PCWP 10.6±2.7mmHg) had significantly higher ePLAR values than post-capillary cases (n=98, 40 male, PAPsys 59.9±17.6mmHg, PAPdiast 25.0±7.4mmHg, PAPmean 38.1±9.8mmHg, PCWP 23.5±6.4mmHg)-ePLAR 0.44±0.22m/s vs 0.20±0.11m/s (p<0.001). ePLAR values were significantly lower in isolated post-capillary pulmonary hypertension than in combined pre- and post-capillary cases (0.18±0.08m/s vs 0.28±0.18m/s, p<0.001). CONCLUSIONS: ePLAR is a simple echocardiographic parameter which can accurately differentiate the smaller subset of patients with pre-capillary pulmonary hypertension from the more common post-capillary aetiology. The use of this easily obtained echocardiographic parameter has the potential to enhance non-invasive triage of patients for specific pulmonary vasodilator therapy.

Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy.

Ruxolitinib is a novel inhibitor of the Janus kinase (JAK) pathway that has become available for the treatment of myelofibrosis. There are increasing reports of opportunistic infections associated with ruxolitinib therapy. We present a case of Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. Clinicians should consider the use of pneumocystis prophylaxis when using ruxolitinib.