Kenneth M. Kral

Continuous Intravenous Epoprostenol for Pulmonary Hypertension Due to the Scleroderma Spectrum of Disease: A Randomized, Controlled Trial

Pulmonary hypertension is characterized by progressive elevation of pulmonary artery pressure and vascular resistance, often leading to right ventricular failure and death (1-3). Continuous intravenous infusion of epoprostenol improves prognosis and symptoms in patients with primary (idiopathic) pulmonary hypertension (4-8). Randomized, controlled clinical trials of epoprostenol for secondary pulmonary hypertension have not been conducted. Pulmonary hypertension frequently complicates the scleroderma spectrum of disease, which includes diffuse scleroderma, limited scleroderma (the CREST syndrome [calcinosis cutis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangectasia]), and the overlap syndrome. These multisystem diseases are characterized by connective tissue and vascular abnormalities; vascular lesions are prominent in all affected tissues (9). Pulmonary hypertension occurs in up to 33% of patients with diffuse scleroderma and 10% to 50% of those with the CREST syndrome (10, 11), in which it is one of the leading causes of death (12, 13). Pulmonary hypertension in the scleroderma spectrum of disease may be associated with interstitial pulmonary fibrosis or may consist of a direct involvement of small and medium-sized pulmonary arteries and arterioles with smooth-muscle hyperplasia, medial hypertrophy, and intimal proliferation (10, 13, 14). Principal involvement of the pulmonary vasculature is more common in the CREST syndrome, whereas patients with pulmonary hypertension and diffuse scleroderma more often have interstitial lung disease (13). No therapies have been proven effective for pulmonary hypertension secondary to the scleroderma spectrum of disease. Small numbers of patients have responded to captopril (15), nifedipine (16-20), and prazosin. In a short-term study of intravenous epoprostenol in seven patients with scleroderma (two with diffuse scleroderma and five with limited scleroderma), six had a decrease in mean pulmonary artery pressure and pulmonary vascular resistance (21). In a small study of pulmonary hypertension secondary to connective tissue disease, long-term infusion therapy with a prostacyclin analogue, iloprost, resulted in improvement in New York Heart Association (NYHA) functional class and quality of life but a variable hemodynamic response (22). Results from a single-center, uncontrolled study suggest that long-term, continuously infused epoprostenol therapy can produce hemodynamic and symptomatic responses in patients with connective tissue disease who have severe pulmonary hypertension that is refractory to conventional medical therapy (23). The rationale for using continuous epoprostenol infusion to treat pulmonary hypertension secondary to the scleroderma spectrum of disease was based on the efficacy of this therapy for primary pulmonary hypertension (4-8) and recognition that scleroderma is a disease characterized by vasospasm and structural changes in the walls of blood vessels. Prostacyclin is a naturally occurring substance produced by vascular endothelium that has vasodilating, antiplatelet aggregation, and cytoprotective effects (24-33). Endogenous production of prostacyclin is decreased in an animal model of neonatal pulmonary hypertension (34) and in adult humans with pulmonary hypertension (35). Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in patients with primary pulmonary hypertension (36). Endothelial dysfunction also plays an important role in the vascular manifestations of the scleroderma spectrum of disease (37, 38), including the Raynaud phenomenon and digital ischemia, which cause considerable morbidity. Calcium-channel blockers (39-45), enalapril (46), and intermittent intravenous infusions of prostacyclin (47-49) and iloprost (50-54) improve the Raynaud phenomenon in some patients. Mixed results have been obtained with oral prostacyclin analogues (55, 56), and a recent multicenter trial of oral iloprost showed no benefit (57). The effect of long-term, continuously infused epoprostenol on the severity of the Raynaud phenomenon and on digital ulcer counts has not been previously evaluated. Our 12-week multicenter, open-label, randomized study was designed to determine whether the beneficial effect of epoprostenol seen in patients with primary pulmonary hypertension could be extended to patients with pulmonary hypertension secondary to the scleroderma spectrum of disease. Our objective was to evaluate the effects of continuous infusion of epoprostenol on exercise capacity in patients with pulmonary hypertension secondary to the scleroderma spectrum of disease. A secondary objective was assessment of the effects of long-term continuous epoprostenol infusion on cardiopulmonary hemodynamics, Borg Dyspnea Score, Dyspnea-Fatigue Rating, NYHA functional class, survival, and safety. Vasospastic manifestations, such as the Raynaud phenomenon and digital ulcerations, were also followed. Methods Patient Selection Eligible patients had pulmonary hypertension secondary to the scleroderma spectrum of disease in accordance with the inclusion and exclusion criteria summarized in Table 1. For the purposes of this study, the scleroderma spectrum of disease was defined as systemic sclerosis with diffuse or limited scleroderma (58); systemic sclerosis that overlapped with another connective tissue disease; or the presence of definite features of systemic sclerosis, including the Raynaud phenomenon and positive test result for antinuclear antibody, plus positive test results for anticentromere antibody, anti-Scl 70 antibody, or nailfold capillary abnormalities. Systemic sclerosis with limited cutaneous involvement (the CREST syndrome) was defined as the presence of any three of the following conditions: subcutaneous calcinosis, the Raynaud phenomenon, esophageal dysfunction (defined clinically), sclerodactyly, or telangectasia. Patients with interstitial lung disease of a more than mild degree were not included in the study because such patients were thought to be less likely to show benefit. Table 1. Key Inclusion and Exclusion Criteria On the basis of a previous 12-week study of the effects of epoprostenol infusion in patients with severe primary pulmonary hypertension (6) and using the 6-minute walk test as the primary outcome measure, we calculated that 50 patients per treatment group would provide 80% power to detect a difference of 50 meters in the average change from baseline, at an level of 0.05 (two-tailed t-test). Randomization and Treatment The protocol was approved by the institutional review boards of the 17 participating centers. After giving informed consent, 111 eligible patients were randomly assigned (1:1) to receive continuous epoprostenol infusion (Flolan, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina) plus conventional therapy or to receive conventional therapy alone. Investigators contacted a central randomization center to obtain treatment assignment, which was based on a stratified randomized block design. Assignments were stratified on the basis of vasodilator use at baseline (yes or no) and exercise capacity at baseline (50 to<200 m or 200 m) and were randomized within blocks. Fifty-six patients were assigned to receive epoprostenol plus conventional therapy, and 55 patients were assigned to receive conventional therapy alone. Investigators were not blinded to treatment group assignment; however, independent blinded observers assessed the primary efficacy measure, exercise capacity. Patients taking calcium-channel blockers at study entry continued to take them during the study period. Adjustments in concomitant medications were allowed during the study on the basis of clinical judgment. Patients in both groups were to receive oral anticoagulants during the study; 94 of the 111 enrolled patients took warfarin. Venous access for epoprostenol infusion (in the epoprostenol group only) was obtained by insertion of a permanent indwelling central venous catheter. Epoprostenol was infused continuously by a portable infusion pump (CADD-1 Model 5100 HF, SIMS Deltec, St. Paul, Minnesota). Patients were instructed in sterile technique, catheter care, and drug preparation and administration. Epoprostenol therapy was initiated at a low dose (usually 2 ng/kg of body weight per minute). During the 12-week study, doses were adjusted on the basis of signs or symptoms consistent with persistent pulmonary hypertension in the absence of intolerable adverse effects (Figure 1). Figure 1. Epoprostenol dosing. Outcome Measures The primary measure of efficacy was exercise capacity, as defined by the distance a patient could walk in 6 minutes. Trained observers at each site who were not otherwise involved in patient care administered the 6-minute walk test. All patients wore an ambulatory infusion pump and a hospital gown over their clothes to mask the presence or absence of a long-term indwelling catheter, thereby blinding testers to the patients treatment groups. Each patient performed one practice walk test. A standardized, unencouraged 6-minute walk test was performed as described elsewhere (59) at baseline and at 1, 6, and 12 weeks. The 6-minute walk test has been shown to provide meaningful outcome data in assessing potential therapy for patients with pulmonary hypertension (6). Secondary measures of efficacy were cardiopulmonary hemodynamics measured by performing right-heart catheterization using standard techniques at baseline and week 12; the Borg Dyspnea Score (60), obtained immediately after completion of the 6-minute walk test at baseline and 1, 6, and 12 weeks (6, 59); the Dyspnea-Fatigue Rating, obtained before the 6-minute walk test at baseline and weeks 1, 6, and 12 (61); NYHA functional class (62), measured at baseline and weeks 1, 6, and 12; digital ulcer counts, done at baseline and weeks 6 and 12; and the severity of the Raynaud phenomenon, assessed

Meta-analysis: Effects of Adding Salmeterol to Inhaled Corticosteroids on Serious Asthma-Related Events

Context Guidelines recommend adding long-acting -agonists to regimens of patients with asthma that is not controlled on inhaled corticosteroids alone. Is this safe? Contribution This meta-analysis summarizes 66 GlaxoSmithKline trials involving 20966 patients with persistent asthma. Trials compared twice-daily salmeterol, 50 g, plus inhaled corticosteroids with inhaled corticosteroids alone. Combination therapy did not appear to alter risk for asthma-related hospitalizations but did decrease risk for severe exacerbations requiring systemic corticosteroids. The only cases of asthma-related death and intubation occurred in patients receiving combination therapy. Caution Most trials were short and originally designed to assess lung function rather than clinical outcomes. The Editors Asthma is a chronic disease affecting nearly 20 million people in the United States and approximately 300 million people worldwide (1). In response to the growing burden of uncontrolled asthma, evidence-based guidelines were released in the early 1990s to bridge the gap between research and practice, with the objective of improving management. National and international asthma guidelines recommend that all patients with persistent asthma receive regular treatment with anti-inflammatory medication, preferably an inhaled corticosteroid. For patients whose asthma is not controlled by inhaled corticosteroids alone, guidelines recommend adding a long-acting -agonist (1, 2). Recently, concern about the role of long-acting -agonists in asthma management was raised in a randomized, observational study of more than 26000 patients (3). In this study, salmeterol compared with placebo added to usual therapy showed a small but statistically significant increase in severe asthma-related events, including asthma-related death. In contrast, the largest casecontrolled study to date of 532 asthma deaths (4) concluded that use of long-acting -agonists was not associated with increased risk for asthma-related death compared with other therapies. The Cochrane Airways Group has published several meta-analyses of clinical trials that studied the combination of inhaled corticosteroids and long-acting 2-agonists and concluded that exacerbations of asthma were infrequent and occurred at similar or lower rates in participants receiving concurrent long-acting -agonists and inhaled corticosteroids than in those receiving inhaled corticosteroids alone (57). Salpeter and colleagues (8) performed a meta-analysis examining life-threatening or fatal asthma exacerbations in participants using long-acting -agonists. Approximately 50% of the participants did not receive concurrent inhaled corticosteroid therapy, and the results showed that, although rare, asthma-related hospitalization and death occurred more frequently in participants receiving long-acting -agonists than in those receiving placebo. Because asthma guidelines clearly state that long-acting -agonists should be taken concurrently with inhaled corticosteroids (1, 2), we conducted a meta-analysis of published and unpublished GlaxoSmithKline trials that evaluated use of salmeterol and inhaled corticosteroids compared with inhaled corticosteroid monotherapy alone. Methods Data Sources and Searches We reviewed all studies posted as of September 2007 to the GlaxoSmithKline Clinical Trials Registry (ctr.gsk.co.uk/welcome.asp) for the following GlaxoSmithKline drugs: fluticasone propionate/salmeterol (Advair), salmeterol xinafoate (Serevent), and fluticasone propionate (Flovent). This registry is a repository of data from GlaxoSmithKline-sponsored clinical trials. We also searched MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews from 1982 to September 2007. These searches were not restricted to studies published in English. Terms included salmeterol, -agonist, long-acting -agonist, inhaled corticosteroids, fluticasone propionate, budesonide, triamcinolone acetonide, beclomethasone dipropionate, randomized, controlled clinical trial, asthma, Advair, and Seretide. Finally, we supplemented these searches by reviewing references from published reviews. Study Selection Three reviewers perused the GlaxoSmithKline registry and search outputs (titles and abstracts) to identify randomized, controlled trials that compared the use of inhaled corticosteroids plus salmeterol with inhaled corticosteroids alone in patients with asthma. We selected randomized, double-blind, parallel-design, long-term dosing studies (range, 1 to 52 weeks) that used the approved dosage of salmeterol (50 g twice daily) in the United States and had been completed and analyzed by 30 September 2007. We did not exclude any trials on the basis of language. We excluded uncontrolled, open-label studies; single-dose studies; and crossover studies. Data Extraction and Quality Assessment One reviewer extracted information about participants, interventions, and comparisons from trials in the GlaxoSmithKline database, registry, or publications, and a second reviewer doubled-checked this information. One reviewer extracted information about trials that were not sponsored by GlaxoSmithKline. We did not use a specific checklist or scale to assess the quality of the trials: Protocols for the GlaxoSmithKline trials met the International Conference on Harmonisation guidelines. For these trials, a participant could spontaneously report adverse events. Study personnel solicited these participants by regular interviews and asked standardized, open-ended questions about any changes in their health status. The interval for these interviews was defined by the individual protocols but generally did not exceed 4 weeks. All GlaxoSmithKline trials report case narratives of serious adverse events, which include hospitalization, intubation, or death. We sent case narratives of reported serious adverse events that occurred during the randomized, double-blind phase of the GlaxoSmithKline trials to 3 physicians. These physicians, who were blinded to drug assignment in each case, independently reviewed the narratives and adjudicated the asthma relationship for hospitalization, intubation, and death status of each case. Any disagreements about adjudications were resolved through consensus of the 3 physicians. Statistical Analysis We used 2 methods to pool GlaxoSmithKline data on asthma-related hospitalizations and severe asthma-related exacerbations that required systemic corticosteroids. First, we calculated risk differences by using data from GlaxoSmithKline trials that met inclusion criteria (even those without events). We applied a treatment group continuity correction for trials in which at least 1 of the treatment groups had no events. In sensitivity analyses, we used 0.01, 0.001, and 0.0001 continuity corrections (9). Second, we used the Peto odds ratio method, which excludes trials with no events and performs reasonably well when imbalance in trial group size is low, the rate of events is low (1%), and the effect size is small (10, 11). For all estimates, we calculated 95% CIs (12, 13). We used the Cochran Q test and I 2 to evaluate statistical heterogeneity. All analyses were based on fixed-effects models and were conducted with StatsDirect statistical software, version 2.6.6 (Sale, United Kingdom) (14). Role of the Funding Source GlaxoSmithKline sponsored most trials summarized in this review. GlaxoSmithKline also supported data collection, analyses, manuscript preparation, and data interpretation for the review. All authors approved the manuscript for submission. Results Of 1218 reports identified in the combined searches, we found 80 randomized trials that compared salmeterol plus inhaled corticosteroids with inhaled corticosteroids alone (Figure 1). Of these, we excluded 4 short crossover trials that involved a total of 72 participants and 3 open-label trials that included 452 participants. None of the 7 excluded trials reported any asthma-related deaths, intubations, or hospitalizations. One trial (SLGT26) included in the current analysis had 3 groups. We excluded the group that involved 244 participants who were assigned to a dose of salmeterol (100 g twice daily) that exceeded the current recommendation. There were 3 asthma-related hospitalizations but no deaths in this excluded treatment group. Figure 1. Study flow diagram. GSK = GlaxoSmithKline. *Studies could contribute to more than 1 subanalysis. Trial Characteristics Seven trials that were not sponsored by GlaxoSmithKline met eligibility criteria. These trials involved a total of 503 participants (1521). None reported hospitalization, intubation, or death in a participant receiving salmeterol plus inhaled corticosteroids or inhaled corticosteroids alone. Because we did not have access to individual case narratives of adverse events in these trials, we did not include them in the quantitative analyses. The GlaxoSmithKline registry included 66 eligible trials that involved a total of 20966 participants (Appendix Table 1). In these trials, 10400 participants received inhaled corticosteroids plus salmeterol and 10566 received inhaled corticosteroids alone. The median trial duration was 12 weeks (range, 1 to 52 weeks). Sample sizes ranged from 12 to 3416. The mean age of participants was about 38 years. Forty-four percent were men, and 82% were white. Most had moderate to severe persistent asthma. The overall rate of withdrawal for any reason was about 14% among participants receiving inhaled corticosteroids plus salmeterol and about 17% among those receiving inhaled corticosteroids alone. Appendix Table 1. Included Studies Most trials used a lung function measure (FEV1 or peak expiratory flow) as the primary end point. In a few studies, the primary end point was a measure of asthma control, such as exacerbations or symptoms. The largest study (SAM40027) used a composite measure of asthma control that integrated lung function measures as well as symptom control and exacerbations as the primary e

Longterm Survival Among Patients with Scleroderma-associated Pulmonary Arterial Hypertension Treated with Intravenous Epoprostenol

Objective. Pulmonary arterial hypertension (PAH) remains challenging to treat, especially in association with scleroderma. We examined survival rates among patients with PAH in association with scleroderma who received epoprostenol (Flolan®) through continuous intravenous (IV) infusion in an uncontrolled open-label 3-year extension study following an initial randomized, controlled 12-week study. Methods. One hundred two patients diagnosed with PAH in association with scleroderma who received epoprostenol were included in the analyses. This included 51 PAH patients from a subject population of 56 who received epoprostenol in the randomized controlled study, and 46 patients from an initial population of 55 subjects on conventional therapy in the randomized controlled study, who received epoprostenol in the extension study. All patients in this extension study received open-label epoprostenol. Adverse events, survival, and dosing information were collected throughout the study. Results. The probabilities of survival during the first and second years for all subjects who received epoprostenol during the initial randomized controlled study or during the extension study were 0.71 and 0.52, respectively. This measure remained constant at 0.48 during the third and fourth years. Conclusion. This study reports longterm survival rates for patients with scleroderma-associated PAH treated with IV epoprostenol. Although comparisons to historical data should be made with caution, this study reports a better survival outcome than natural history data on patients with scleroderma-associated PAH.

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone.

BACKGROUNDnThe safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate.nnnMETHODSnIn this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation.nnnRESULTSnOf 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001).nnnCONCLUSIONSnPatients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group. (AUSTRI ClinicalTrials.gov number, NCT01475721.).

Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma

BACKGROUNDnLong-acting beta-agonists (LABAs) have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children.nnnMETHODSnWe randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. The statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis.nnnRESULTSnAmong the 6208 patients, 27 patients in the fluticasone-salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone-salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01).nnnCONCLUSIONSnIn this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).