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.

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.

Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist.

OBJECTIVE: Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis (SSc; scleroderma) and lead to pain, impaired function, and tissue loss. We investigated whether treatment with the endothelin receptor antagonist, bosentan, decreased the development of new digital ulcers in patients with SSc. METHODS: This was a randomized, prospective, placebo-controlled, double-blind study of 122 patients at 17 centers in Europe and North America, evaluating the effect of treatment on prevention of digital ulcers. The primary outcome variable was the number of new digital ulcers developing during the 16-week study period. Secondary assessments included healing of existing digital ulcers and evaluation of hand function using the Scleroderma Health Assessment Questionnaire. RESULTS: Patients receiving bosentan had a 48% reduction in the mean number of new ulcers during the treatment period (1.4 versus 2.7 new ulcers; P = 0.0083). Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 (P = 0.0075). In patients receiving bosentan, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in the healing of existing ulcers. Serum transaminase levels were elevated to >3-fold the upper limit of normal in bosentan-treated patients; this elevation is comparable with that observed in previous studies of this agent. Other side effects were similar in the 2 treatment groups. CONCLUSION: Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc. Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving hand function in patients with SSc.

Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.

BACKGROUND: Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. FINDINGS: In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. INTERPRETATION: Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from the European Epidemiologic Registry of Cystic Fibrosis.

Data derived from a cross-sectional analysis of 7,566 patients stratified into six age groups were used to compare lung function, body mass index (BMI), and weight for age in patients with and without cystic fibrosis-related diabetes mellitus (CFDM). The presence of CFDM was tightly linked to poor lung function, regardless of age. The mean value of FEV(1) % predicted in the age groups < 10, 10-< 15, 15-< 20, 20-< 25, 25-< 30, and 30 years or older were 87%, 77%, 69%, 58%, 55%, and 53% in the nondiabetic cystic fibrosis (CF) patients as compared to 79%, 66%, 55%, 49%, 46%, and 44% in the diabetic CF patients. BMI and weight for age were also lower in diabetic than nondiabetic CF patients in all age groups, except for BMI in the youngest patients. The difference in lung function and in nutritional parameters between diabetic and nondiabetic CF patients was not linked to presence or absence of any specific pathogen in the lower respiratory tract. These results confirm and extend those of earlier studies in smaller numbers of patients, and they clearly identify CFDM as a powerful determinant of severe lung disease and reduced survival in patients with CF and diabetes mellitus.

Factors associated with poor pulmonary function: cross-sectional analysis of data from the ERCF. European Epidemiologic Registry of Cystic Fibrosis.

The European Epidemiologic Registry of Cystic Fibrosis began collecting longitudinal data on European cystic fibrosis patients in 1994. A cross-sectional analysis was performed to identify the factors associated with low values of % predicted forced expiratory volume in one second (FEV1) upon patient enrollment. Data from 7,010 patients aged > or =6 yrs were included. Clinical conditions, microbiological isolates and medications reported at enrollment or within the following 180 days were analysed for age-specific associations. Factors associated with FEV1 that were lower by >10% of pred values were: lower weight for age percentiles, haemoptysis, pneumothorax, pulmonary symptoms at presentation, Pseudomonas aeruginosa, Burkholderia cepacia, oral corticosteroids, nonsteroid anti-inflammatory drugs, dornase alfa, oxygen and assisted ventilation and, in patients >12 yrs old only, use of airway clearance techniques, inhaled bronchodilators, oral nutritional supplements, pancreatic enzymes and insulin or oral hypoglycaemics. Slightly impaired lung function (5-10%) was associated with: diabetes (> or = 18-yrs-old), gastro-oesophageal reflux, allergic bronchopulmonary aspergillosis, asthma-like symptoms, portal hypertension, Aspergillus spp. and Candida spp. Sex, Haemophilus influenzae and Staphylococcus aureus were not associated with impaired pulmonary status. Regular exercise (especially in older patients) and nasal polyposis were associated with slightly better FEV1. The results confirm those of previous studies and suggest selective prescribing in sicker patients.

A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period.

BACKGROUND: Chronic endobronchial sepsis and profuse airway secretions dominate pulmonary disease in cystic fibrosis. Recombinant human DNase I (dornase alfa) reduces the viscoelasticity of airway secretions and hence may improve clearance of airway secretions. OBJECTIVES: To evaluate the long-term influence of dornase alfa on disease progression by performing a case-controlled study with dornase alfa over a period of 4 years. METHODS: A cohort of patients with cystic fibrosis who have been treated with dornase alfa were matched with a control group of patients with cystic fibrosis who had not received treatment with dornase alfa. The patients were matched by pulmonary function, age, and then sex. All available measurements of forced expiratory volume in one second (FEV1), height, weight and sputum bacteriology were collected for periods when the patients were free from respiratory exacerbations. RESULTS: Thirty-eight patients were matched. Slopes of median changes in FEV1 were -2.19 (-3.32, -1.06) in the control group and -0.75 (-1.87, 0.36) in the dornase alfa-treated group (p = 0.076). There were more infective exacerbations per patient year in the control group [3.13 (1.25-4.25)] in comparison to the dornase alfa group [1.25 (0.63-3.0), p = 0.035] over the 4-year treatment period. Antibiotic requirements were also greater with a median 43.75 (17.5-60.0) days of intravenous antibiotic use per patient year in the control group and 16.25 (8.5-44.0) days in the dornase alfa group (p = 0.034). CONCLUSIONS: The trends suggest that dornase alfa may have some influence on disease progression but in view of the limitations of the current study the need for further long-term studies in larger cohorts of patients is emphasised.

European Epidemiologic Registry of Cystic Fibrosis (ERCF): comparison of major disease manifestations between patients with different classes of mutations.

SUMMARY. By August 1997, 11,749 patients with cystic fibrosis had been enrolled in the European Epidemiologic Registry of Cystic Fibrosis (ERCF). Genotype analysis had been performed on 8,963 (76%) of these patients, and the majority had one or two identifiable mutations. Patients with known mutations were classified according to the type of mutation (Classes I-V), and were grouped according to the class of mutation on both chromosomes. This resulted in six subgroups, including all patients homozygous for Class I (I/I, n = 72), for Class II (II/II, n = 5,020), and for Class III mutations, (III/III, n = 23). Since there were only 23 patients homozygous for Class III mutations, a fourth group was made up of patients who were compound heterozygous for a Class II and III mutation (II/III, n = 265). There were only five patients homozygous for Class IV mutations, and consequently a fifth group was made up of all patients carrying at least one Class IV mutation, regardless of the nature of the mutation on the other chromosome (IV/any, n = 187). None were homozygous for Class V mutations; consequently, a sixth group consisted of patients carrying at least one Class V mutation (V/any, n = 22). Mean age was highest in groups III/III, IV/any, and V/any (15.6, 16, and 17 years, respectively) as opposed to 12.4 years in group II/II and 13.4 in group II/III, but both group III/III and V/any were small, and the confidence interval of the mean was large. The percentage of patients receiving pancreatic enzymes was lower in groups IV/any and V/any than in any of the other groups, i.e., approximately 50% of patients 18 years or older in both groups as opposed to between 90-100% of all other patients regardless of age. The prevalence of diabetes mellitus increased with age from 2.6% in patients < 18 years to 22.1% in patients 18 years or older in the large group II/II, but was only 1.5% in patients 18 years or older in group IV/any. Disregarding the small group III/III, abnormally elevated liver enzymes and/or bilirubin (1.5 x upper normal limit) was much less frequent in group IV/any than in any of the other groups, both overall and in patients aged 18 years or more. The course of lung disease appeared to be less dependent on genotype than pancreatic function, with only minor differences between groups; however, the mean values of both FVC % and FEV(1) % were slightly higher in group IV/any than all other groups in both younger and older patients. The same was found for the prevalence of some major clinical signs of severe lung disease, such as clubbing, hyperinflation, and crepitations. Overall mean weight expressed as an age percentile was markedly higher in group IV/any than in any other group, which may be related to the finding of a much lower prevalence of chronic P. aeruginosa infection in patients 18 years or older belonging to group IV/any (and V/any) than in any other group. In conclusion, the presence of a class IV mutation appears to offer some degree of protection against pancreatic insufficiency, diabetes mellitus, and liver disease. We confirmed that lung disease follows a milder clinical course in patients with a class IV mutation and that the presence of a class IV mutation (and possibly class V) is associated with a delay in the onset of P. aeruginosa infection.

Allergic bronchopulmonary aspergillosis in cystic fibrosis. A European epidemiological study. Epidemiologic Registry of Cystic Fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a disease resulting from a hypersensitivity response to Aspergillus fumigatus, although the pathogenesis of the disease is unknown and its prevalence in cystic fibrosis (CF) is still poorly defined. Data from the Epidemiologic Registry of Cystic Fibrosis (ERCF) on 12,447 CF patients gathered from 224 CF centres in nine European countries were analysed. The ERCF definition of ABPA diagnosis is a positive skin test and serum precipitins to A. fumigatus, together with serum immunoglobulin (Ig)E levels >1,000 U x mL(-1) and additional clinical or laboratory parameters. The overall prevalence of ABPA in the ERCF population was 7.8% (range: 2.1% in Sweden to 13.6% in Belgium). Prevalence was low <6 yrs of age but was almost constant approximately 10% thereafter. No sex differences were observed. ABPA affected 8.0% of patients with a deltaF508/deltaF508 genotype and 5-6% with deltaF508/G551D, deltaF508/G542X and deltaF508/N1303K genotypes. ABPA patients presented a lower forced expiratory volume in one second (FEV1) than those without ABPA at any age and the prevalence ranged from 6.6% in patients with FEV1 > or =20-12.9% in those with FEV1 <40%. ABPA was associated with higher rates of microbial colonization, pneumothorax and massive haemoptysis, and with higher IgG serum levels and poorer nutritional status. A mixed model regression analysis of lung function showed that FEVI decline during the follow-up period was not substantially different in ABPA patients compared with non-ABPA patients for any subgroups based on age or disease severity at enrollment. To conclude, allergic bronchopulmonary aspergillosis is a frequent complication in cystic fibrosis patients, particularly after the age of 6 yrs, and it is generally associated with a poorer clinical condition. However, any clear independent influence of allergic bronchopulmonary aspergillosis on the rate of lung function decline in the short term was not shown.

The detection of antibodies to recombinant interferon alfa-2a in human serum.

Three different procedures have been used for detecting antibodies to Roferon-A (recombinant human interferon alfa-2a, rHuIFN alpha-2a) in the serum of patients who received this interferon as part of ongoing clinical trials: an antiviral neutralization bioassay (ANB), the standard method recommended by the World Health Organization (WHO), and the more recently developed radioimmunoassay (RIA) and enzymeimmunoassay (EIA). Although the three tests are based on different principles, the correlation among them was excellent. The assays show differences in sensitivities with the ANB being the least sensitive of the three. The EIA equals the RIA in sensitivity, reproducibility, accuracy and labor and provides the advantage of safety and convenience in the use of non-radioactive materials. Therefore, the EIA has been selected as the most suitable assay for initial screening of the sera of patients receiving Roferon-A for the presence of antibodies to this interferon. EIA positive sera are then tested in the ANB to determine whether or not neutralizing activities are present.

Structural analysis of a set of socioeconomic indexes as an aid in defining the socioeconomic level of a family: results from an italian multicentric survey.

The study of possible associations between social and health factors was one of the purposes of the multicentric Italian survey of perinatal preventive medicine. To get a concise and coherent social indicator, which could be useful to this study, we explored the socioeconomic information systematically collected on the parents of 12,058 babies born in 1973-1975 in four centres (Trieste, Milan, Parma and Bari), which reflect some of the heterogeneous aspects of Italy. The Correspondence analysis indicated that the seven considered indexes, concerning both parents' education levels and occupations, dwelling quality and the length of father's residence in the area in which the baby was born, were highly and similarly correlated in each centre. The Dynamic cluster analysis enabled us to bring together the socioeconomic profiles of the families into six classes, on the basis of their similarities, which depend only upon the multivariate distribution of the seven categorical variables under study. Therefore, the attained classification not only is independent of whatever score is assigned to the socioeconomic categories but also allows for the strong interactions between the variables and exploits all the available information. Our six classes were found to be rather similar to the six socioeconomic groups (S.E.G.) of the U.K. Registrar General and to show some resemblance to certain social groups defined by other classifications adopted in obstetric and pediatric field. The socioeconomic indicator constructed here should enable us to find out how much, in different areas of Italy, the social classes may account for inequalities in health conditions and care of the mother and her baby.