Safety and feasibility audit of a home-based drug-transitioning approach for patients with pulmonary arterial hypertension: an observational study.

BACKGROUND: Newer endothelin receptor antagonists (ERAs) used to treat patients with pulmonary arterial hypertension (PAH) are associated with fewer drug-drug interactions than bosentan and require less monitoring. This, combined with a pharmacokinetic basis for improved efficacy, means there may be a clinical rationale for changing therapies. However, this can be challenging and few data on its safety in patients with PAH are available. AIMS: At the Royal Free Hospital in London, UK, home-based medication transitioning has been standard practice since 2009 to avoid unnecessary hospital visits for patients, unless there is a clinical imperative. In this audit of standard practice we evaluated the consequences of adopting such a strategy when transitioning PAH patients between ERA therapies. METHODS AND RESULTS: Using a Clinical Nurse Specialist-led, home-based transitioning strategy, 92 patients with PAH were transitioned from bosentan to macitentan or ambrisentan. Observational data were analysed retrospectively. The majority of patients were female with PAH associated with connective tissue disease and their ERA was changed in the hope of improving efficacy. The process was well tolerated with no adverse events associated with the process. Seventeen patients died during the study (macitentan, n = 5; ambrisentan, n = 12). None of the deaths was considered related to ERA treatment. The majority of patients remained clinically stable, based on WHO functional class and exercise capacity. CONCLUSION: An established home-based transitioning strategy can be adopted safely for patients with PAH changing ERA therapies. Most patients remained stable and the therapy change was well tolerated.

Aggressive combination therapy for treatment of systemic sclerosis-associated pulmonary hypertension.

Pulmonary arterial hypertension is an important complication of systemic sclerosis with high mortality but should be regarded as a treatable manifestation of the disease. Management draws on experience from other forms of pulmonary arterial hypertension and benefits from an increasing number of licenced therapies. Outcome is variable but recent clinical trials suggest that combination therapies used early in the disease may be associated with better outcomes. This is important because previous clinical trials using short-term gain in exercise capacity did not show significant benefit compared to that observed for idiopathic or heritable forms of pulmonary arterial hypertension. Thus, it is important to identify cases as early as possible and to manage cases that are in a high-risk group using early combination therapy. This review summarises the most recent analyses of clinical trial data, with a focus on those patients with SSc-associated pulmonary arterial hypertension and provides the evidence base that supports current treatment recommendations for aggressive pulmonary arterial hypertension occurring in systemic sclerosis, including the early use of combination pulmonary arterial hypertension-specific drugs in appropriate cases.

Combined Pulmonary Fibrosis and Emphysema in Scleroderma-Related Lung Disease Has a Major Confounding Effect on Lung Physiology and Screening for Pulmonary Hypertension.

OBJECTIVE: To assess the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) and the effect of CPFE on the pulmonary function tests used to evaluate the severity of SSc-related ILD and the likelihood of pulmonary hypertension (PH). METHODS: High-resolution computed tomography (HRCT) scans were obtained in 333 patients with SSc-related ILD and were evaluated for the presence of emphysema and the extent of ILD. The effects of emphysema on the associations between pulmonary function variables and the extent of SSc-related ILD as visualized on HRCT and echocardiographic evidence of PH were quantified. RESULTS: Emphysema was present in 41 (12.3%) of the 333 patients with SSc-related ILD, in 26 (19.7%) of 132 smokers, and in 15 (7.5%) of 201 lifelong nonsmokers. When the extent of fibrosis was taken into account, emphysema was associated with significant additional differences from the expected values for diffusing capacity for carbon monoxide (DLco) (average reduction of 24.1%; P < 0.0005), and the forced vital capacity (FVC)/DLco ratio (average increase of 34.8%; P < 0.0005) but not FVC. These effects were identical in smokers and nonsmokers. Multivariate analysis showed that the presence of emphysema had a greater effect than echocardiographically determined PH on the FVC/DLco ratio, regardless of whether it was analyzed as a continuous variable or using a threshold value of 1.6 or 2.0. CONCLUSION: Among patients with SSc-related ILD, emphysema is sporadically present in nonsmokers and is associated with a low pack-year history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in patients with SSc-related ILD.

Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study.

BACKGROUND: Systemic sclerosis (SSc) has high mortality and morbidity. Current management focuses on early detection and treatment of organ-based manifestations. AIM: To determine whether the ascertainment of major organ complications of SSc has changed over time and if this is associated with better survival. DESIGN: Retrospective cohort analysis. METHODS: A total of 520 SSc patients, 234 with disease onset between 1990 and 1993 (historical cohort) and 286 with disease onset between 2000 and 2003 (contemporary cohort), were included. Survival and frequency of internal organ complications were compared between the two cohorts. RESULTS: Five-year survival among diffuse cutaneous SSc (dcSSc) patients has improved from 69% in the 1990-93 cohort to 84% in the 2000-03 cohort (P = 0.018), whereas 5-year survival among the limited cutaneous SSc (lcSSc) patients has remained unchanged-93 and 91%, respectively. Sixteen per cent of the lcSSc subjects and 38% of the dcSSc subjects from the contemporary cohort were diagnosed for the clinically significant pulmonary fibrosis compared with 3 and 7%, respectively, of the historical cohort (P < 0.001). Similarly, the diagnosis of pulmonary arterial hypertension was more frequent in the patients from the contemporary cohort (8 and 7% for lcSSc and dcSSc, respectively) compared with [ < 1% (P = 0.002) and 1% (P = 0.148), respectively] the historical cohort. There was no significant difference between the two cohorts in terms of scleroderma renal crisis and cardiac involvement. CONCLUSION: Survival has substantially improved for the diffuse cutaneous subset of SSc with better and more complete ascertainment of lung complications as a result of systematic annual screening.

Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension.

Several prognostic variables have previously been identified in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Specific medical conditions have also been associated with the development and prognosis of CTEPH. Using a national registry, the current authors have assessed the prognostic value of a larger number of variables and have also attempted to validate the clinical importance of previously identified aetiological factors. Baseline information for all 469 CTEPH patients diagnosed in the UK pulmonary hypertension service between January 2001 and June 2006 was collected from hospital records. Although univariate analysis confirmed the prognostic importance of pulmonary resistance, in multivariate analysis gas transfer and exercise capacity predicted pulmonary endarterectomy perioperative mortality. Cardiac index and exercise capacity independently predicted outcome in patients with nonoperable disease. Previous splenectomy was noted in 6.7% of patients, being significantly more common in patients with nonoperable than operable disease (13.7 versus 3.6%). Medical risk factors were not found to predict mortality. In a large national cohort, predictors of outcome in patients with both operable and nonoperable chronic thromboembolic pulmonary hypertension have been identified. These may be useful in planning treatment. The aetiological importance of previously identified medical risk factors has been confirmed, although the current authors were unable to validate their prognostic strength.

Can CCL2 serum levels be used in risk stratification or to monitor treatment response in systemic sclerosis?

OBJECTIVE: The chemokine CCL2 has been consistently found to be up-regulated in systemic sclerosis. To explore the potential value of serum CCL2 measurement in disease assessment, we have compared CCL2 levels with clinical phenotype and investigated effect of therapy on circulating CCL2. METHODS: Serum samples from a well characterised cohort of 94 systemic sclerosis (SSc) patients, 16 patients with primary Raynaud phenomenon and 11 healthy controls were examined by ELISA. Our cohort of patients included 50 patients with limited cutaneous (lc)SSc (20 with lcSSc alone and 30 with pulmonary arterial hypertension-lcSSc), and 44 with diffuse cutaneous (dc)SSc, 30 of which had early-onset dcSSc. RESULTS: Serum levels of CCL2 were increased in both major SSc subsets. In early stage dcSSc 18/30 (60%) cases demonstrated markedly elevated CCL2, and this was associated with anti-topoisomerase or anti-RNA polymerase I/III antibody reactivity, and with greater frequency of major organ-based complications. Elevation of CCL2 serum levels in the lcSSc subset was not associated with pulmonary arterial hypertension, although there was a trend for reduction following treatment with prostacyclin analogues or bosentan. CONCLUSION: These findings suggest that the CCL2/CCR2 axis is a potential therapeutic target in SSc, particularly in the early dcSSc subset. CCL2 measurement may be useful for risk stratification in early stage disease, but its value in disease monitoring is questionable.

Cardiac assessment of patients for haematopoietic stem cell transplantation.

The expanding role of haematopoietic stem-cell transplantation (HSCT) renders the previous policy of avoiding transplantation in high-risk cardiac patients obsolete. Patients with amyloid, autoimmune conditions, sickle-cell disease, or thalassaemia, and patients over the age of 60 years are increasingly being offered HSCT. It is evident that the policy of avoiding transplantation in patients with impaired systolic function fails to identify all high-risk patients in such groups, and will deprive some patients of the benefits of HSCT unnecessarily. The development of an appropriate algorithm for cardiac pre-assessment and peri-transplant management is hampered by an inadequate understanding of the predictive value of various tests of cardiovascular function, the rapid evolution of advanced management strategies for cardiac dysfunction, and the development of non-cardiotoxic conditioning regimens. To meet this need we propose that an algorithm based on evidence from other clinical situations - already been found to be successful in the management of HSCT in patients with systemic sclerosis - should be used uniformly, and registry studies should be undertaken to distinguish those aspects of the algorithm that positively help to expand the remit of HSCT from those that add little of value.

Angiographically proven coronary artery disease in scleroderma.

OBJECTIVE: It has been suggested that macrovascular disease is more common in patients with scleroderma (SSc). We investigated the prevalence of coronary artery disease (CAD) in SSc using coronary angiography. METHODS: Coronary angiography was performed in 172 patients with SSc and suspected CAD to examine the prevalence of significant CAD. The prevalence of CAD was estimated in the whole group and also according to age, gender and type of symptoms (typical angina, atypical angina and non-anginal pain or breathlessness). Standardized prevalence ratios (SPRs) were calculated in each symptomatic group in order to compare CAD rates amongst our observed population with those predicted using the Diamond and Forrester (D & F) probability analysis. This analysis provides an estimate of the probability of CAD based on gender, age and symptoms in subjects aged between 30-69 yrs. RESULTS: The observed prevalence of CAD in the whole population was 22% (38/172); 17% (6/36) in males and 23% (32/136) in females. A total of 41 patients were excluded because they were outside the age range for D & F analysis. Compared with the reference population, the SPRs for CAD in the three SSc groups were: 47% (95% CI 21.7-89.9) in the typical angina group (22 patients), 50% (95% CI 13.6-128) in the atypical angina group (22 patients) and 93% (95% CI 49.4-158.8) in the non-anginal pain or breathlessness group (87 patients). CONCLUSION: The prevalence of CAD in patients with SSc is similar and not greater to that expected in individuals without SSc.

Connective tissue associated pulmonary arterial hypertension.

The number of publications in the field of pulmonary hypertension has increased exponentially over the past 10 years. As a consequence our understanding of the condition has advanced enormously. Pulmonary hypertension is now recognised as an uncommon and treatable disease, rather than a rare lethal disease. Progress in the field of connective tissue disease associated pulmonary hypertension has been less consistent. This paper covers the most influential published data on connective tissue associated pulmonary hypertension, and adds some insights from data available on file with pharmaceutical companies and from our database at the Royal Free Hospital. The following conclusions may be drawn. First, the prevalence of pulmonary hypertension associated with connective tissue diseases is lower than generally accepted. Second, the natural history and prognosis, at least in the setting of systemic sclerosis, is worse than seen in patients with idiopathic pulmonary hypertension. Finally, widespread and timely availability of disease modifying therapies substantially improves the prognosis for patients with systemic sclerosis associated pulmonary hypertension, in the treatment population and consequentially in the population as a whole. Identifying patients with very early disease and analysing the drivers for disease progression, is the key to further progress. Early diagnosis is most readily achieved in patients with connective tissue disease associated pulmonary hypertension. This represents an opportunity for those with an interest in academic rheumatology.

Real-time myocardial contrast dobutamine stress echocardiography in coronary stenosis.

BACKGROUND: Simultaneous wall motion and myocardial perfusion analysis could offer advantages over either method alone. Diagnostic utility of combining these parameters during dobutamine stress echocardiography is evaluated in this study. METHODS: Myocardial contrast dobutamine stress echocardiography was performed on thirty-eight patients with single or double vessel coronary artery stenosis of >50%. Two-dimensional standard wall motion images were acquired at baseline, low, intermediate and peak stages of dobutamine stress echocardiography. Contrast enhanced wall motion and perfusion were assessed with Cadence Contrast Imaging (Sequoia C256, Acuson) and Optison infusion (GE Healthcare) at baseline and peak stages of the same protocol. Perfusion was analysed by identification of contrast defects and by measuring contrast replenishment time after destructive ultrasound pulses. RESULTS: The group consisted of 28 males and 10 females, mean age 60.9+/-9.7 years. Fifty-four out of one hundred and fourteen coronary arteries were affected by stenoses >50%. Standard wall motion analysis was assessable in 37 cases, one of which was inconclusive, while contrast wall motion and perfusion were assessable in 32 cases. Accuracy for coronary stenosis was 84% for standard wall motion (108 coronary territories), 82% for contrast wall motion (96 territories), 69% for peak stress contrast defects (83 territories), 91% for combined peak stress contrast defects and increased contrast replenishment time (85 territories), and 90% for all contrast modalities combined (96 territories). CONCLUSION: Combined wall motion and real-time perfusion assessment during dobutamine stress is feasible and at least equivalent to conventional stress echocardiography for detection of significant coronary stenosis.

Systemic sclerosis associated pulmonary hypertension: improved survival in the current era.

OBJECTIVES: To measure survival, haemodynamic function and functional class in patients with systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) in two treatment eras. METHODS: Six year longitudinal study of 92 consecutive patients with SSc-PAH diagnosed by cardiac catheterisation. Data were collected both prospectively and retrospectively. Patients were given basic treatment (diuretics, digoxin, oxygen and warfarin). Where clinically indicated, a prostanoid was used as advanced treatment (historical control group). From 2002, the range of treatments available expanded to include bosentan, which was generally the preferred treatment (current treatment era group). Survival was measured from the date of diagnosis of pulmonary hypertension by cardiac catheterisation. Six minute walking distance and haemodynamic function were measured at the time of diagnosis and at least one month after treatment was started. RESULTS: The historical control group comprised 47 patients, all of whom received basic treatment; 27 of these were also treated with prostanoids. The current treatment era group comprised 45 patients, all of whom received bosentan as preferred treatment. Kaplan-Meier survival in the historical control group was 68% at one year and 47% at two years. Survival in the current treatment era group was 81% and 71% (p = 0.016) at one and two years, respectively. Pulmonary vascular resistance increased in the historical control group (by 147 dyn.s.cm(-5)), whereas in the current treatment era group, it remained stable over an average of nine months (decrease of 16 dyn x s x cm(-5), p < 0.006). CONCLUSION: Survival of selected patients with SSc-PAH has improved in the current treatment era. In contrast to patients treated historically with basic drugs and prostanoids, patients treated in the current treatment era had improved survival associated with a lack of deterioration in cardiac haemodynamic function.

The myth of pulmonary Raynaud's phenomenon: the contribution of pulmonary arterial vasospasm in patients with systemic sclerosis related pulmonary arterial hypertension.

OBJECTIVE: To investigate the contribution of cold induced pulmonary vasospasm by peripheral and central cold stimulus in exacerbating pulmonary arterial hypertension (PAH) in patients with systemic sclerosis undergoing cardiac catheterisation. METHODS: In a prospective pilot study, 21 patients with systemic sclerosis and catheter proven PAH had mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac output (CO) measured before and after peripheral (hand immersion into cold water at 10-15 degrees C for two minutes if tolerated) and central (direct cold water at 4 degrees C injected into the right atrium) cold pressor challenge. Markers of endothelial activation, platelet function, and nitric oxide degradation were measured in blood sampled from the pulmonary artery. RESULTS: 19 of the patients (mean (SD) age, 56 (4) years; baseline mPAP, 34 (8) mm Hg; PVR, 420 (87) dyne.s.cm(-5); CO, 6.4 (1.8) l/min) tolerated cold hand immersion for the maximum two minute duration. All 21 tolerated central cold pressor challenge (three to five injections of 10 ml saline boluses at 4 degrees C). There was no significant change in haemodynamics after cold challenge by either route of provocation. Levels of endothelin-1, von Willebrand factor, fibrinogen, and 3-nitrotyrosine were raised compared with control values in patients with systemic sclerosis but without PAH, but did not change significantly after peripheral cold challenge. CONCLUSIONS: Pulmonary vasospasm in response to peripheral and centrally administered cold pressor challenge is unlikely to contribute to persistence of pulmonary arterial hypertension in patients with systemic sclerosis.

A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism.

Evidence suggests that endothelin may have a fundamental role in scleroderma pathogenesis, including pulmonary arterial hypertension (PAH)--a leading cause of death in patients with scleroderma. Development of a new class of drug, endothelin receptor antagonists, heralds an improved outlook for patients with scleroderma and related diseases. Heightened vigilance towards early detection of PAH in scleroderma and a multidisciplinary approach to diagnosis and treatment may improve clinical outcomes for these patients.

Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVE: A prospective study to evaluate echocardiography and gas transfer (DLCO) by comparison with cardiac catheterization in discriminating between patients with and without systemic sclerosis-associated pulmonary arterial hypertension (SScPAH). METHOD: A total of 137 (52 with and 85 without pulmonary fibrosis) had echocardiography and lung function tests within 3 months of their definitive invasive study. RESULTS: At cardiac catheterization 99 of these patients were found to have PAH, while PAH was excluded in 38. Echocardiographically estimated tricuspid gradient (TG) showed a moderate positive correlation (r(2) = 0.44, P<0.005) with both mean pulmonary pressure and invasively determined tricuspid gradient. DLCO showed a weak correlation (r(2 )= 0.09, P = 0.006), when compared with mean pulmonary arterial pressure. In total, 97% of patients with an echocardiographically determined TG of > 45 mmHg were found to have pulmonary hypertension at catheterization. However, no threshold could be defined with either screening test that safely excluded PAH. CONCLUSIONS: The positive predictive accuracy of currently used non-invasive tests are adequate for the diagnosis of advanced PAH provided sufficiently high thresholds (TG > 45 mmHg or DLCO < 55% predicted) are used. These tests cannot be relied upon to exclude pulmonary hypertension where pre-test probability is high.

Significance of plasma N-terminal pro-brain natriuretic peptide in patients with systemic sclerosis-related pulmonary arterial hypertension.

OBJECTIVES: A single centre pilot study to investigate the role of the plasma N-terminal pro-brain natriuretic peptide (N-T proBNP) assay to risk stratify patients with suspected pulmonary arterial hypertension (PAH) from a background SSc population. METHODS: Out of 49 SSc patients, 23 had and 26 did not have PAH. Right ventricular haemodynamic variables, six-minute walk test and plasma N-T proBNP levels were recorded from patients catheterised for suspected PAH (23 with PAH and 11/26 without PAH). RESULTS: Mean value of N-T proBNP for SSc patients with PAH was 3365 (standard error 1095) pg/ml compared to 347 (174) pg/ml for patients without PAH. There was a statistically significant correlation (P < 0.05) between N-T proBNP values and (i) mean pulmonary artery pressure (r = 0.53), (ii) right ventricular end diastolic pressure (r = 0.59) and (iii) pulmonary vascular resistance (r = 0.49). Receiver operator characteristic curve analysis showed that a cut-off value of 395.34 pg/ml had a sensitivity of 0.69 and specificity of 1.0. CONCLUSIONS: N-T proBNP estimation in systemic sclerosis-related pulmonary hypertension is a potentially useful diagnostic tool with a high specificity and negative predictive value. This test has the potential to have an important role in risk stratification and monitoring of therapy in the future.

Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach.

OBJECTIVE: To determine the prevalence of systemic sclerosis associated pulmonary arterial hypertension (SScPAH), evaluate outcome, and identify predictors of mortality in a large patient cohort. METHODS: A prospective four year follow up study of 794 patients (722 from our own unit and 72 referrals). All patients screened for PAH using a combination of echocardiography, lung function testing, and clinical assessment. Patients with suspected raised pulmonary artery systolic pressures of >35 mm Hg, carbon monoxide transfer factor (TLCO) <50% predicted, or a precipitous fall in TLCO >20% over a one year period with no pulmonary fibrosis, and patients with SSc with breathlessness with no pulmonary fibrosis found were investigated with right heart catheterisation. All patients with SScPAH were treated in accordance with current best practice. RESULTS: The prevalence of PAH was 12% (89/722) by right heart catheter. The survival was 81%, 63%, and 56% at 1, 2, and 3 years from the diagnosis (in 89 patients from our own cohort and 59/72 referrals). Haemodynamic indices of right ventricular failure--raised mRAP (hazard ratio 21), raised mPAP (hazard ratio 20), and low CI (hazard ratio 11) predicted an adverse outcome There was no significant difference in survival between patients with SScPAH with (n=40) and without (n=108) pulmonary fibrosis (p=0.3). CONCLUSIONS: The prevalence of SScPAH in this cohort was similar to that of other catheter based studies and lower than that of previous echo based studies. The 148 patients with SScPAH actively treated had comparable outcomes to those of the cohorts with primary pulmonary hypertension. A high mRAP was the strongest haemodynamic predictor of mortality. To improve prognosis, future treatments need to be implemented at an earlier disease stage to prevent right ventricular decompensation.