Mortality trends in pulmonary arterial hypertension in Canada: a temporal analysis of survival per ESC/ERS guideline era.

BACKGROUND: The evolution in pulmonary arterial hypertension (PAH) management has been summarised in three iterations of the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. No study has assessed whether changes in management, as reflected in the changing guidelines, has translated to improved long-term survival in PAH. METHODS: We performed a mixed retrospective/prospective analysis of treatment-naïve, incident PAH patients (n=392) diagnosed at three major centres in Canada from 2009 to 2021. Patients were divided into two groups based on their diagnosis date and in accordance with the 2009 and 2015 ESC/ERS guideline iterations. Overall survival was assessed based on date of diagnosis and initial treatment strategy (i.e. monotherapy versus combination therapy). RESULTS: There was a shift towards more aggressive upfront management with combination therapy in Canada after the publication of the 2015 ESC/ERS guidelines (10.4% and 30.8% in patients from 2009 to 2015 and 36.0% and 57.4% in patients diagnosed after 2015 for baseline and 2-year follow-up, respectively). A key factor associated with combination therapy after 2015 was higher pulmonary vascular resistance (p=0.009). The 1-, 3- and 5-year survival rates in Canada were 89.2%, 75.6% and 56.0%, respectively. Despite changes in management, there was no improvement in long-term survival before and after publication of the 2015 ESC/ERS guidelines (p=0.53). CONCLUSIONS: There was an increase in the use of initial and sequential combination therapy in Canada after publication of the 2015 ESC/ERS guidelines, which was not associated with improved long-term survival. These data highlight the continued difficulties of managing this aggressive pulmonary disease in an era without a cure.

Association Between the Pulmonary Artery Pulsatility Index and Prognosis in Pulmonary Arterial Hypertension: A Multicentre Study.

Background: Risk stratification is fundamental in the management of pulmonary arterial hypertension (PAH). Pulmonary artery pulsatility index (PAPi), defined as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), is a hemodynamic index shown to predict acute right ventricular (RV) dysfunction in several settings. Our objective was to test the prognostic utility of PAPi in a diverse multicentre cohort of patients with PAH. Methods: A multicentre retrospective cohort study of consecutive adult patients with a new diagnosis of PAH on right heart catheterization between January 2016 and December 2020 was undertaken across 4 major centres in Canada. Hemodynamic data, clinical data, and outcomes were collected. The association of PAPi and other hemodynamic variables with mortality was assessed by receiver-operating characteristic curves and Cox proportional hazards modeling. Results: We identified 590 patients with a mean age of 61.4 ± 15.5 years, with 66.3% being female. A low PAPi (defined as < 5.3) was associated with higher mortality at 1 year: 10.2% vs 5.2% (P = 0.02). In a multivariable model including age, sex, body mass index, and functional class, a low PAPi was associated with mortality at 1 year (area under the curveof 0.64 (95% confidence interval 0.55-0.74). However, high RAP (> 8 mm Hg) was similarly predictive of mortality, with an area under the curve of 0.65. Conclusion: PAPi was associated with mortality in a large incident PAH cohort. However, the discriminative value of PAPi was not higher than that of RAP alone.

Contexte: La stratification des risques est fondamentale dans la prise en charge de l'hypertension artérielle pulmonaire (HTAP). L'indice de pulsatilité des artères pulmonaires (iPAP), défini comme la pression différentielle dans les artères pulmonaires divisée par la pression auriculaire droite (PAD), est un indice hémodynamique qui s'est révélé prédictif d'une dysfonction ventriculaire droite (VD) aiguë dans plusieurs situations. Notre objectif était d'évaluer l'utilité pronostique de l'iPAP dans une cohorte multicentrique diversifiée de patients atteints d'HTAP. Méthodologie: Une étude de cohorte multicentrique rétrospective de patients adultes consécutifs atteints d'une HTAP nouvellement diagnostiquée par cathétérisme cardiaque droit entre janvier 2016 et décembre 2020 a été effectuée dans quatre grands centres au Canada. Les données hémodynamiques, les données cliniques et les résultats ont été recueillis. La corrélation de l'iPAP et d'autres va-riables hémodynamiques avec la mortalité a été évaluée par les courbes caractéristiques opérationnelles du receveur et des modèles à risques proportionnels de Cox. Résultats: Nous avons recensé 590 patients dont l'âge moyen était de 61,4 ± 15,5 ans; la proportion de femmes était de 66,3 %. Un faible iPAP (défini comme une valeur < 5,3) a été associé à une hausse de la mortalité à 1 an : 10,2 % contre 5,2 % (p= 0,02). Dans un modèle multivarié comprenant l'âge, le sexe, l'indice de masse corporelle et la classe fonctionnelle, un faible iPAP a été associé à la mortalité à 1 an (aire sous la courbe de 0,64 [intervalle de confiance à 95 %; de 0,55 à 0,74]). Cependant, une PAD élevée (> 8 mmHg) a aussi été un facteur prédictif de mortalité, l'aire sous la courbe étant de 0,65. Conclusions: L'iPAP a été associé à la mortalité dans une vaste cohorte de patients atteints d'une HTAP. Toutefois, la valeur discriminante de l'iPAP n'a pas été supérieure à celle de la PAD seule.

Ventricular-arterial decoupling is associated with in-hospital adverse events in normotensive pulmonary embolism.

During acute pulmonary embolism (PE) a compensatory increase in right ventricular (RV) contractility is required to match increased afterload to maintain right ventricular-pulmonary arterial (RV-PA) coupling. The aim of this study was to assess the prognostic utility of RV-PA decoupling in acute PE. We assessed the association between measures of transthoracic echocardiography (TTE)-derived RV-PA coupling including tricuspid annular plane systolic excursion (TAPSE)/right ventricular systolic pressure (RVSP) and right ventricular fractional area change (FAC)/RVSP as well as stroke volume index (SVI)/RVSP (a measure of pulmonary artery capacitance) with adverse PE-related events (in-hospital PE-related mortality or cardiopulmonary decompensation) using logistic regression analysis. In 820 normotensive patients TTE-derived markers of RV-PA coupling were associated with PE-related adverse events. For each 0.1 mm/mmHg decrease in TAPSE/RVSP the odds of an adverse event increased by 2.5-fold [adjusted OR (aOR) 2.49, 95% confidence interval (CI) 1.46-4.24, p = 0.001], for every 0.1%/mmHg decrease in FAC/RVSP the odds of an adverse event increased by 1.4-fold (aOR 1.42, CI 1.09-1.86, p = 0.010), and for every 0.1 mL/mmHg m2 decrease in SVI/RVSP the odds of an event increased by 2.75-fold (aOR 2.78, CI 1.72-4.50, p < 0.001). In multivariable analysis, TAPSE/RVSP and SVI/RVSP were independent of other risk stratification methods including computed tomography-derived right ventricular dysfunction (RVD), the Bova score, and subjective assessment of TTE-derived RVD. In patients with normotensive acute PE, TTE-derived measures of RV-PA coupling are associated with adverse in-hospital PE-related events and provide incremental value in the risk assessment beyond computed tomography-derived RVD, the Bova score, or subjective TTE-derived RVD.

Upfront riociguat and ambrisentan combination therapy for newly diagnosed pulmonary arterial hypertension: A prospective open-label trial.

BACKGROUND: Initial combination therapy with an endothelin receptor antagonist (ERA) and riociguat in pulmonary arterial hypertension (PAH) has limited supporting data. METHODS: We performed a prospective, single-arm, open-label trial of riociguat, and ambrisentan for incident PAH patients in functional class III. The primary endpoint was pulmonary vascular resistance (PVR) at 4-months. RESULTS: Twenty patients (59 ± 13 years old, 85% female) enrolled and 1 died before their 4-month follow-up. Fifteen patients completed a 4-month and 13 completed the 12-month follow-up. At 4-months PVR decreased 54% with an absolute change of -5.8 Wood units (95% CI -4.0; -7.5, p < 0.001). Other hemodynamic variables and risk scores also improved. Six patients discontinued riociguat and 8 discontinued ambrisentan, with 5 (25%) discontinuing both. CONCLUSIONS: These results do not support the routine use of riociguat plus ambrisentan in initial regimens. Future studies are needed to compare this strategy with phosphodiesterase-5 inhibitors and an ERA with respect to tolerability and long-term outcomes.

Rapid prediction of adverse outcomes for acute normotensive pulmonary embolism: derivation of the Calgary Acute Pulmonary Embolism score.

BACKGROUND: Acute pulmonary embolism (PE) has a wide spectrum of outcomes, but the best method to risk-stratify normotensive patients for adverse outcomes remains unclear. METHODS: A multicentre retrospective cohort study of acute PE patients admitted from emergency departments in Calgary, Canada, between 2012 and 2017 was used to develop a refined acute PE risk score. The composite primary outcome of in-hospital PE-related death or haemodynamic decompensation. The model was internally validated using bootstrapping and the prognostic value of the derived risk score was compared to the Bova score. RESULTS: Of 2067 patients with normotensive acute PE, the primary outcome (haemodynamic decompensation or PE-related death) occurred in 32 (1.5%) patients. In simplified Pulmonary Embolism Severity Index high-risk patients (n=1498, 78%), a multivariable model used to predict the primary outcome retained computed tomography (CT) right-left ventricular diameter ratio ≥1.5, systolic blood pressure 90-100 mmHg, central pulmonary artery clot and heart rate ≥100 beats·min-1 with a C-statistic of 0.89 (95% CI 0.82-0.93). Three risk groups were derived using a weighted score (score, prevalence, primary outcome event rate): group 1 (0-3, 73.8%, 0.34%), group 2 (4-6, 17.6%, 5.8%), group 3 (7-9, 8.7%, 12.8%) with a C-statistic 0.85 (95% CI 0.78-0.91). In comparison the prevalence (primary outcome) by Bova risk stages (n=1179) were stage I 49.8% (0.2%); stage II 31.9% (2.7%); and stage III 18.4% (7.8%) with a C-statistic 0.80 (95% CI 0.74-0.86). CONCLUSIONS: A simple four-variable risk score using clinical data immediately available after CT diagnosis of acute PE predicts in-hospital adverse outcomes. External validation of the Calgary Acute Pulmonary Embolism score is required.

Characterization of Right Ventricular Deformation in Pulmonary Arterial Hypertension Using Three-Dimensional Principal Strain Analysis.

BACKGROUND: Pulmonary arterial hypertension (PAH) can cause maladaptive right ventricular (RV) functional changes associated with adverse prognosis that are challenging to accurately quantify noninvasively. The aim of this study was to explore principal strain (PS) with contraction angle analysis using three-dimensional echocardiography to characterize RV deformation changes in patients with PAH. METHODS: Three-dimensional echocardiography was performed in 37 patients with PAH and 20 healthy control subjects with two-component (primary and secondary) PS and principal contraction angle analysis. Patients were stratified according to World Health Organization (WHO) functional class. RESULTS: Primary PS differed significantly between patients with PAH and healthy control subjects (-20.2 ± 3.3% vs -26.8 ± 3.3%, P = .01), while secondary PS was not significantly different (3.6 ± 5.1% vs -2.5 ± 4.7%, P = .12). Principal contraction angle was significantly lower in patients with PAH (63 ± 22° vs 71 ± 7°, P = .01), with the greatest reduction for the RV free wall. Primary PS and principal contraction angle differed significantly between WHO class I and II and class III and IV patients (-23.9 ± 4.7% vs -18.1 ± 4.8% [P = .03] and 69 ± 9° vs 58 ± 14° [P = .03], respectively), while secondary PS was not significantly different between groups (P = .13). Compared with healthy control subjects, septal principal contraction angle was not different in patients with WHO class I and II PAH (P = .62), but it was significantly reduced in those with WHO class III and IV PAH (P < .01). The area under the curve for primary PS to differentiate patients with PAH by WHO functional class was 0.81 (95% CI, 0.77-0.89; P = .01). Primary PS intraclass correlation coefficients for intraobserver and interobserver variability were 0.91 (95% CI, 0.88-0.93) and 0.86 (95% CI, 0.81-0.88), respectively. CONCLUSIONS: PS analysis using three-dimensional echocardiography provides comprehensive quantification of RV deformation and characterizes alterations occurring in PAH that are associated with WHO functional class.

A Prospective Evaluation of the Diagnostic Accuracy of the Physical Examination for Pulmonary Hypertension.

BACKGROUND: The usefulness of physical examination findings for pulmonary hypertension (PH) is not well established. The purpose of this study was to evaluate prospectively the diagnostic performance of the physical examination for detecting PH. METHODS: Consecutive patients undergoing right-sided heart catheterization (n = 116) were examined by an attending physician, medical resident, and medical student in a blinded fashion. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) were calculated for each physical finding. Jugular venous pulsation (JVP) height was compared with right atrial pressure (RAP) by using linear regression. The association between physical findings and PH was assessed using univariate and multivariate logistic regression. RESULTS: The prevalence of PH was 87%. Only a JVP > 3 cm (positive LR, 2.5; 95% CI, 1.2-5.4) and pulmonic regurgitation murmur (specificity, 100%; 95% CI, 79%-100%) helped rule in PH. The absence of JVP > 3 cm (negative LR, 0.4; 95% CI, 0.3-0.6) and absence of loud pulmonic component of the second heart sound (negative LR, 0.5; 95% CI, 0.3-0.9) had modest usefulness in excluding PH. JVP correlated with RAP (r = 0.59; P < .001) but tended to lead to underestimation of RAP (mean bias, -3.4 cm H2O; 95% limits of agreement, -14.0 to 7.2). The presence of JVP > 3 cm and a parasternal heave discriminated PH (area under the curve [AUC] = 0.75). The combination of JVP > 3 cm, heave, and peripheral edema discriminated severe PH (mean pulmonary arterial pressure ≥ 45 mm Hg; AUC = 0.82). CONCLUSIONS: Individual physical examination findings have inadequate diagnostic usefulness for PH. No combination of findings can be used to exclude PH, but the presence of high JVP, peripheral edema, and parasternal heave suggests severe PH.

Pulmonary arterial hypertension secondary to adult-onset Still's disease: Response to cyclosporine and sildenafil over 15 years of follow-up.

Adult onset Still's disease (AOSD) is an autoimmune disease characterized by systemic inflammation and is a rarely reported cause of pulmonary arterial hypertension (PAH). We describe the clinical course of a 40-year-old woman who presented with PAH 19 months after a diagnosis of AOSD. Sildenafil and immunosuppressive therapy with cyclosporine resulted in clinical and hemodynamic improvement with long-term survival 15 years after her initial presentation of AOSD. We review the literature for published cases of PAH due to AOSD and discuss the potential mechanisms relating inflammatory diseases and PAH.

Epidemic Pseudomonas aeruginosa infection in patients with cystic fibrosis is not a risk factor for poor clinical Outcomes following lung transplantation.

BACKGROUND: Epidemic strains of Pseudomonas aeruginosa (ePA) causing infection in cystic fibrosis (CF) have been commonly identified from clinics around the world. ePA disproportionally impacts CF patient pre-transplant outcomes manifesting in increased exacerbation frequency, worsened treatment burden and increased rate of lung function decline, and disproportionally leads to death and/or transplantation. As other CF factors such as pre-transplant infection with multi-resistant organisms, and isolation of P. aeruginosa in the post transplant graft, may impact post-transplant outcomes, we sought to determine if infection with ePA similarly adversely impact post-transplant outcomes. METHODS: Between 1991-2014, 53 CF patients from our center received lung transplants. Bacterial strain typing was performed retrospectively on isolates collected prior to transplantation. Comprehensive chart reviews were performed to obtain baseline patient characteristics and post-transplant outcomes. RESULTS: Of the 53 transplanted patients, 57% of patients were infected with ePA prior to transplant; the other 43% of patients had unique strains of P. aeruginosa. Mean age at transplant was 29.0years for ePA and 33.3years for unique (p=0.04). There were no differences in overall survival (HR=0.75, 95% CI 0.31-1.79), bronchiolitis obliterans syndrome (BOS) free survival (HR 1.43, 95% CI 0.54-4.84) or all other assessed outcomes including exacerbation frequency, chronic renal failure, acute cellular rejections, Aspergillus infection, airway stenosis, and post-transplant lymphoproliferative disorder. CONCLUSION: Unlike pre-transplant outcomes, CF patients infected with ePA do not experience worse post-transplant outcomes than those infected with unique strains. Therefore, lung transplantation should be considered for all patients with P. aeruginosa infection and end stage lung disease, irrespective of infection with ePA.

Sildenafil treatment of primary pulmonary hypertension.

A 37-year-old woman with primary pulmonary hypertension and worsening symptomatology underwent pulmonary artery (PA) catheterization and vasodilator trials. Oxygen had no effect, but 10 parts/million of nitric oxide reduced mean PA (PAm) pressure by 20%. Prostacyclin infusion at 8 ng/kg/min decreased the PAm pressure by 11%, but further dose increases were limited by systemic hypotension. Sildenafil in doses of 25 mg or higher resulted in an average decrease of 14% in PAm pressure. Sildenafil is a potentially useful treatment option for patients with primary pulmonary hypertension, and further investigation is warranted.

Diagnostic evaluation and management of chronic thromboembolic pulmonary hypertension: a clinical practice guideline.

BACKGROUND: Pulmonary embolism is a common condition. Some patients subsequently develop chronic thromboembolic pulmonary hypertension (CTEPH). Many care gaps exist in the diagnosis and management of CTEPH patients including lack of awareness, incomplete diagnostic assessment, and inconsistent use of surgical and medical therapies. METHODS: A representative interdisciplinary panel of medical experts undertook a formal clinical practice guideline development process. A total of 20 key clinical issues were defined according to the patient population, intervention, comparator, outcome (PICO) approach. The panel performed an evidence-based, systematic, literature review, assessed and graded the relevant evidence, and made 26 recommendations. RESULTS: Asymptomatic patients postpulmonary embolism should not be screened for CTEPH. In patients with pulmonary hypertension, the possibility of CTEPH should be routinely evaluated with initial ventilation/perfusion lung scanning, not computed tomography angiography. Pulmonary endarterectomy surgery is the treatment of choice in patients with surgically accessible CTEPH, and may also be effective in CTEPH patients with disease in more 'distal' pulmonary arteries. The anatomical extent of CTEPH for surgical pulmonary endarterectomy is best assessed by contrast pulmonary angiography, although positive computed tomography angiography may be acceptable. Novel medications indicated for the treatment of pulmonary hypertension may be effective for selected CTEPH patients. CONCLUSIONS: The present guideline requires formal dissemination to relevant target user groups, the development of tools for implementation into routine clinical practice and formal evaluation of the impact of the guideline on the quality of care of CTEPH patients. Moreover, the guideline will be updated periodically to reflect new evidence or clinical approaches.

Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study.

BACKGROUND: There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants. METHODS: We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of chi(2) tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis. FINDINGS: We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3.6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22.4%) given antivirals later (p=0.007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar. INTERPRETATION: Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009-10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation. FUNDING: None.