Recognition of pulmonary hypertension in the rheumatology community: lessons from a Quality Enhancement Research Initiative.

OBJECTIVES: The aim of this study was to utilise the Quality Enhancement Research Initiative in Systemic Sclerosis (QuERI-SSc) to measure and reduce a perceived gap in the diagnosis of pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc). METHODS: Rheumatologists enrolled patients with SSc (aged ≥ 18 years) and provided data on a panel of diagnostic tests over 3 years. Pulmonary function testing, echocardiography, 6-minute walk distance, N-terminal pro-brain natriuretic peptide assays, high-resolution computed tomography of the lungs, and ventilation/perfusion scan plus right heart catheterisation (RHC; when appropriate) were emphasised. Exclusion criteria included previously documented PAH, interstitial lung disease, and SSc overlapping with other connective tissue disease. RESULTS: Participating rheumatologists enrolled 207 patients with SSc (90% female; 80% white), with a median age of 57 years and median disease duration of 5 years. A total of 82% of patients were classified as New York Heart Association functional class I and II; of these patients, 177 had an echocardiogram at enrolment and 191 at any time during the study. Of those who met study-specified criteria for RHC at enrolment, only 3 of 7 patients underwent RHC. CONCLUSIONS: The screening algorithm was successful in identifying patients with mild impairment. Although specific tools were recommended for screening PAH in patients with SSc, results indicate that significant diagnostic care gaps still exist in the general rheumatology community. Better understanding and adherence to guidelines could improve the care and, ideally, outcomes of these high-risk patients.

Looking to the future: a new decade of pulmonary arterial hypertension therapy.

Pulmonary arterial hypertension (PAH) is a severe and debilitating disease characterised by vascular proliferation and remodelling of the small pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance, increased afterload on the right ventricle and, ultimately, right heart failure. Although there is no "cure" for PAH, the availability of targeted therapies over the past decade has led to major advances in the management of PAH, reflected in improvements in survival in the modern treatment era. However, despite this, disease progression is inevitable in the majority of patients with PAH and overall the long-term prognosis, although improved, remains poor. There is a clear and urgent need for new therapeutic options, either through the development of improved drugs that act on targets established by existing PAH-specific therapies, or of agents targeting novel pathogenic pathways not addressed by currently available therapies. A number of such new agents that have shown promise in experimental models and preliminary human studies are discussed in this article.

Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis.

Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of CTDs. In patients with SSc, PAH has a dramatic impact on prognosis and survival and is the single most common cause of disease-related death.Yearly echocardiographic screening for PAH is recommended in patients with SSc. If suspected, confirmation of PAH diagnosis by right heart catheterization is necessary. Treatment goals for patients with PAH associated with SSc (PAH-SSc) aim to slow disease progression and improve quality of life. Some measures used to gauge the effect of treatment in patients with PAH-SSc remain to be fully validated; the 6-min walk distance, for example, is a simple and reproducible means of assessing exercise capacity, but there exists a need to understand what constitutes a clinically relevant change in this specific patient population. Currently, pharmacological intervention in PAH-SSc may target one or more of three pathophysiological pathways in PAH. The prostacyclin analogue epoprostenol has been shown to improve exercise capacity and haemodynamics in PAH-SSc patients and similar data are available from smaller studies on trepostinil and iloprost. The dual endothelin receptor antagonist bosentan has been shown to improve exercise capacity and haemodynamics in PAH-SSc, and similar data have been obtained in small numbers of patients treated with the endothelin receptor A antagonists sitaxsentan and ambrisentan. Impaired production of nitric oxide may be addressed by inhibiting phosphodiesterase type-5 with sildenafil or possibly tadalafil. Combinations of multiple targeted therapies may be beneficial to this patient population.

Cardiac complications of systemic sclerosis.

The majority of patients with SSc are believed to have subclinical primary cardiac involvement. Overt cardiac manifestations of SSc are associated with poor prognosis and can be difficult to manage. Primary myocardial disease, i.e. without systemic or pulmonary hypertension and without significant pulmonary or renal disease, is postulated to be due to microvascular ischaemia. Undetected early cardiac manifestations can progress silently to myocardial fibrosis. Symptoms may manifest without warning and can rapidly lead to arrhythmia and left and right heart dysfunction and failure. Of the currently practical screening methods, annual echocardiography and/or evaluation of N-terminal portion of pro-B-type natriuretic peptide concentrations should therefore be employed in SSc patients, in order to anticipate the development of cardiac symptoms. Although there is limited evidence in respect of specific therapeutic options, treatment of early abnormalities with calcium channel blockers and angiotensin-converting enzyme inhibitors may improve myocardial perfusion and function, while standard management of overt cardiac disease is equally appropriate in the SSc population. However, it remains to be seen if early intervention can limit the progression of these life-threatening complications.

Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension.

PURPOSE: Treprostinil is approved for the treatment of pulmonary arterial hypertension (PAH) via continuous intravenous (IV) infusion. Treprostinil's anti-platelet aggregation characteristics and stability at room temperature may allow for low infusion rates (0.1-0.2 mL/hr) using a miniaturized infusion pump. METHODS: A 12-week, multi-center, open-label study in 12 adult PAH patients, evaluated the feasibility and safety of low-flow IV treprostinil administration via the 407C miniaturized pump. Patients receiving IV treprostinil at a stable dose were transitioned from their current CADD-Legacy pump to the 407C and were assessed for adverse events including catheter occlusions, pump alarms, and efficacy (six minute walk distance (6MWD), Borg Dyspnea Score (BDS), NYHA functional class, and PAH signs/symptoms). All patients were also maintained on therapeutic doses of warfarin, heparin or low molecular weight heparin throughout the study. RESULTS: Baseline mean (+/-SD) 6MWD was 477 +/- 76 m (n = 9) with mean BDS of 2.1 +/- 1.2 (n = 9). Week 12 mean 6MWD and BDS were 500 +/- 92 m and 2.3 +/- 1.7, respectively (n = 9). Four patients discontinued the study prematurely (3 AEs and 1 consent withdrawn). Adverse events included headache, flushing, and nausea. Pump complications occurred in 5 of 12 patients, and although no catheter occlusions occurred in any patient during the 12-week study, further study is needed regarding pump complications. CONCLUSION: This study demonstrates that treprostinil can be administered intravenously at infusion rates as low as 0.1 mL/hr for 12 weeks without catheter occlusions. Further studies are warranted because the potential for adverse events is of some concern.

Survival in patients with pulmonary arterial hypertension treated with first-line bosentan.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease of the small pulmonary arteries and arterioles, characterized by intimal fibrosis, medial hypertrophy and plexiform lesions. When untreated both the idiopathic form (IPAH, formerly termed primary pulmonary hypertension, PPH) and PAH related to various other conditions such as scleroderma (SSc) often take a progressive course with high mortality. There is ongoing search for disease-specific treatments that are able to improve survival in these patients. The oral dual endothelin (ET(A)/ET(B)) antagonist bosentan has been shown to improve exercise capacity, time to clinical worsening, haemodynamics and quality of life in short-term studies. MATERIALS AND METHODS: To determine the long-term effects of bosentan on survival, patients from the two double-blind, randomized trials and their open-label extensions, treated with first-line bosentan, were followed for up to 3 years. Data on survival were collected between September 1999 (first patient included in the placebo-controlled trials) and December 2002. Vital status was verified in each patient. The survival cohorts of these patients were compared with either the predicted survival for each patient based on an equation from the National Institutes of Health (NIH) PPH registry or with historical controls. RESULTS: Observed survival up to 36 months was reported as a Kaplan-Meier estimate in three cohorts: (1) In 169 PPH patients treated with first-line bosentan, 1- and 2-year survival was 96% and 89%, respectively, vs. predicted untreated survival at 1 and 2 years of 69% and 57%, respectively; (2) in 50 patients with PAH associated with SSc (PAH-SSc), 1-, 2- and 3-year survival was 82%, 67% and 64%, respectively, vs. approximately 45%, approximately 35% and approximately 28%, respectively, from registry data of untreated PAH-SSc patients; and (3) in 139 PPH patients in WHO functional class III, 1- and 2-year survival was 97% and 91%, respectively, vs. 91% and 84% in a historical cohort of 346 patients treated with epoprostenol in five major referral centres. CONCLUSIONS: The present analyses suggest that first-line bosentan therapy, followed by the addition of other disease-specific therapies as required, improves survival in patients with advanced PAH.

Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol.

BACKGROUND: The oral dual endothelin receptor antagonist bosentan improves exercise capacity and delays clinical worsening in patients with pulmonary arterial hypertension, but its use could delay starting intravenous epoprostenol, a life saving treatment. METHODS: Survival in patients with functional class III idiopathic pulmonary arterial hypertension (PAH) treated with bosentan in clinical trials was compared with historical data from similar patients treated with epoprostenol in the clinic. Statistical methods were used to adjust for possible underlying differences between the two groups. RESULTS: Baseline factors for the 139 patients treated with bosentan and the 346 treated with epoprostenol suggested that the epoprostenol cohort had more severe disease-that is, a lower cardiac index (2.01 v 2.39 l/min/m2) and higher pressures and resistance. Kaplan-Meier survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan cohort and 91% and 84% in the epoprostenol cohort. Cox regression analyses adjusting for differences in baseline factors showed a greater probability of death in the epoprostenol cohort (hazard ratio 2.2 (95% confidence interval 1.2 to 4.0) in the model adjusted for haemodynamics). Alternative regression analyses and analyses to adjust for different data collection dates gave consistently similar results. When matched cohorts of 83 patients each were selected, survival estimates were similar. In the bosentan cohort 87% and 75% of patients followed for 1 and 2 years, respectively, remained on monotherapy. CONCLUSIONS: No evidence was found to suggest that initial treatment with oral bosentan, followed by or with the addition of other treatment if needed, adversely affected the long term outcome compared with initial intravenous epoprostenol in patients with class III idiopathic PAH.

The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect.

BACKGROUND: PAH trials traditionally use 6MW as the primary endpoint. Concerns regarding a "ceiling effect" masking efficacy have led to exclusion of patients with milder disease from most trials (BL 6MW>450 m). STRIDE I evaluated the selective endothelin A receptor antagonist, sitaxsentan (SITAX), in a 12-week randomized, double-blind, trial (178 patients) employing placebo (PBO), 100 mg or 300 mg SITAX orally once daily in PAH and included patients with NYHA class II, congenital heart disease and a BL 6MW>450 m, groups often excluded from previous trials. METHODS: We analyzed 6MW effects For All Pts (intention-to treat) and those meeting Traditional enrollment criteria, defined as patients with NYHA class III or IV and 6MW< or =450 m at BL with idiopathic PAH or PAH related to connective tissue disease. The 100 mg and 300 mg SITAX arms are pooled based on similar treatment effects on 6MW. CONCLUSION: Existence of a "ceiling effect" is supported by these data. The magnitude of the treatment effect and statistical power when using 6MW as the endpoint. Comparisons between PAH trials that do not adjust for the effects of differing enrollment criteria require caution.

Survival with first-line bosentan in patients with primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a progressive disease with high mortality. Administration of i.v. epoprostenol has demonstrated improved exercise tolerance, haemodynamics, and survival. The orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. To determine the effect of first-line bosentan therapy on survival, this study followed 169 patients with PPH treated with bosentan in two placebo-controlled trials and their extensions. Data on survival and alternative treatments were collected from September 1999 (start of the first placebo-controlled study) to December 31, 2002. Observed survival up to 36 months was reported as Kaplan-Meier estimates and compared with predicted survival as determined for each patient by the National Institutes of Health Registry formula. Kaplan-Meier survival estimates were 96% at 12 months and 89% at 24 months. In contrast, predicted survival was 69% and 57%, respectively. In addition, at the end of 12 and 24 months, 85% and 70% of patients, respectively, remained alive and on bosentan monotherapy. Factors that predicted a worse outcome included World Health Organization Functional Class IV and 6-min walk distance below the median (358 m) at baseline. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

Stenting to reverse left ventricular ischemia due to left main coronary artery compression in primary pulmonary hypertension.

Angina is a common symptom of severe pulmonary hypertension. Although many theories for the source of this pain have been proposed, right ventricular ischemia is the one most commonly accepted as the cause. We report on two patients with primary pulmonary hypertension who had angina with normal activity or on provocation. One patient had severe left ventricular dysfunction. Both were found to have severe ostial stenosis of the left main coronary artery as a result of compression from a dilated pulmonary artery. Both patients underwent stenting of the left main coronary artery with excellent angiographic results, and complete resolution of the signs and symptoms of angina and left ventricular ischemia. Left ventricular ischemia due to compression of the left main coronary artery may be a much more common mechanism of angina and left ventricular dysfunction in patients with pulmonary hypertension than previously acknowledged. Stenting of the coronary artery can be done safely with the resolution of these symptoms.

Severe pulmonary hypertension: critical care clinics.

Pulmonary hypertension has many causes and therapies. A meticulous evaluation is critical. Substantial advances in medical therapy have occurred over the past decade, and the future treatment of this syndrome is promising, with many new medications on the horizon.

Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial.

BACKGROUND: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial. OBJECTIVE: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease. DESIGN: Randomized, open-label, controlled trial. SETTING: 17 pulmonary hypertension referral centers. PATIENTS: 111 patients with moderate to severe pulmonary hypertension. INTERVENTION: Epoprostenol plus conventional therapy or conventional therapy alone. MEASUREMENTS: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival. RESULTS: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg [CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute [CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition). CONCLUSIONS: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.

Severe pulmonary hypertension associated with COPD.

Pulmonary hypertension can be associated with chronic obstructive pulmonary disease (COPD). Mild to moderate elevations in pulmonary artery pressures are commonly reported. Previous studies included patients initially diagnosed with COPD and subsequently evaluated for pulmonary hypertension. The occurrence of COPD in patients being evaluated for pulmonary hypertension has not been reported. We performed a retrospective chart review of approximately 600 patients evaluated in a large tertiary care pulmonary hypertension clinic. Subjects were included if they were older than 40 years, had no other secondary causes of pulmonary hypertension and had evidence of COPD by pulmonary function studies or thoracic computed tomography. Criteria was met by five subjects (3 males and 2 females, mean age = 65 years) all of whom were past smokers. The average mean pulmonary artery pressure (MPAP) was 59 +/- 7 mm Hg. The mean pulmonary vascular resistance (PVR) was 15.2 +/- 5 mmHg/liter/min. Only one patient had a fall in MPAP of more than 10% and a greater than 30% decline in PVR following infusion of adenosine to test vasodilator responsiveness. COPD is rare in a population referred primarily for evaluation of pulmonary hypertension. Although infrequent, severe pulmonary hypertension may be associated with COPD.

The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension.

OBJECTIVES: This study evaluated the response to prostacyclin dose reduction in patients with primary pulmonary hypertension (PPH) who developed high cardiac outputs. BACKGROUND: Patients on prostacyclin require chronic upward dose titration to overcome tolerance to the medication. No upper limit of effective dose has been described. METHODS: We studied 12 patients with PPH treated with chronic prostacyclin therapy who presented in high cardiac output states. Each patient underwent prostacyclin dose reduction under hemodynamic guidance targeted to reduce the cardiac index to < or =4 liter/min/M2, unless rebound pulmonary hypertension occurred. Following dose reduction, patients were observed for changes in the effectiveness of the prostacyclin. RESULTS: Patients were treated for 39 +/- 20 months, resulting in a 71% reduction in pulmonary vascular resistance compared to baseline. At the time of their most recent evaluation their cardiac outputs were increased to 10.1 +/- 2.3 liter/min. The patients underwent a 39% dose reduction (range 12% to 78%) resulting in a change of mean PAP from 45 to 46 mm Hg (p = NS), cardiac index from 7.4 +/- 1.4 to 4 +/- 0.74 liter/min/M2 (p = 0.01), and pulmonary vascular resistance from 3.7 +/- 1.7 to 4.7 +/- 1.5 units (p < 0.001). In no instance did rebound pulmonary hypertension occur. However, the patients all retained their clinical benefit without a return of tolerance. CONCLUSIONS: Excessive prostacyclin in PPH can lead to a high cardiac output state, suggesting it has important positive inotropic effects. In this circumstance, reducing the dose can allow the cardiac output to return to normal without worsening the clinical state.

Utility of electron beam computed tomography to stratify patients presenting to the emergency room with chest pain.

One hundred thirty-four patients presenting to the emergency room with the chief complaint of chest pain were studied with electron beam computed tomography scan. Electron beam computed tomography scanning had a 98% negative predictive value in this setting.

Development of nonspecific interstitial pneumonitis associated with long-term treatment of primary pulmonary hypertension with prostacyclin.

A young woman with primary pulmonary hypertension presented with interstitial lung disease approximately 5 years after successful treatment with IV prostacyclin. The pathology was consistent with nonspecific interstitial pneumonitis and was unresponsive to steroids and immunosuppressive medications. We speculate that further cases of this syndrome may be reported as more patients are living beyond 5 years with prostacyclin.

Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: a case series.

BACKGROUND: Treatment of patients with secondary pulmonary hypertension has been unsatisfactory. OBJECTIVE: To describe exercise capacity, functional class, and hemodynamic variables after long-term intravenous infusion of prostacyclin in patients with secondary pulmonary hypertension. DESIGN: Case series. SETTING: Academic referral center. PATIENTS: 33 patients with secondary, precapillary pulmonary hypertension (New York Heart Association class III or IV). INTERVENTION: Continuous intravenous prostacyclin administered by portable infusion pump on a compassionate-use basis. MEASUREMENTS: Functional class, treadmill time, and hemodynamic variables. RESULTS: Patients were followed for an average of 12.7 +/- 5.6 months. Exercise tolerance and New York Heart Association class improved in each patient. The duration of treadmill exercise increased from 186 seconds to 491 seconds, an increase of 305 seconds (95% CI, 194 to 417 seconds; P < 0.001). Mean pulmonary artery pressure decreased from 60 mm Hg to 46 mm Hg, a decrease of 14 mm Hg (CI, 9 to 19 mm Hg; P < 0.001). Cardiac output increased from 3.90 L/min to 6.30 L/min, an increase of 2.40 L/min (CI, 1.56 to 3.25 L/min; P < 0.001). The pulmonary vascular resistance decreased from 1143 dynes x s/cm5 to 575 dynes x s/cm5, a decrease of 567 dynes x s/cm5 (CI, 407 to 727 dynes x s/cm5; P < 0.001). Patients with collagen vascular disease, congenital heart disease, and portopulmonary hypertension were analyzed with other patients and separately. All groups had a statistically significant reduction in mean pulmonary artery pressure and a statistically significant increase in cardiac output. CONCLUSION: Intravenous prostacyclin may be effective in the treatment of patients with certain types of secondary pulmonary hypertension.

Penicillin resistance in laboratory isolates of Streptococcus pneumoniae, in Western Australia, 1990-1994.

Increasing frequency of penicillin resistance in Streptococcus pneumoniae has been reported worldwide. We report on clinical isolates of penicillin-resistant pneumococci (PRP) in Western Australia (WA) from 1990-1994. A retrospective survey of laboratories performing susceptibility testing, or receiving isolates referred from rural areas found resistant on oxacillin disc screening, was undertaken. Four of 11 laboratories could provide data for the five year time period inclusive. Information was provided on susceptibility to penicillin, type of specimen, date of isolation and; age, sex and race of individuals with PRP. Penicillin resistance increased from 1.3% to 9.0% over the five year period. PRP were rarely invasive. Highest age specific rates per 100,000 were found in children < 5 years (19.4) and adults > or = 60 years (5.1). Aboriginal ethnicity was associated with resistance. The increasing frequency of PRP in WA indicates the need for surveillance systems for their detection.