Steven D. Nathan

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

Treatment of idiopathic pulmonary fibrosis with Ambrisentan: A parallel, randomized trial

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant

Pulmonary hypertension (PH) may complicate idiopathic pulmonary fibrosis (IPF) but the prevalence of PH in IPF remains undefined. The present authors sought to describe the prevalence of PH in IPF. The lung transplant registry for the USA (January 1995 to June 2004) was analysed and IPF patients who had undergone right heart catheterisation (RHC) were identified. PH was defined as a mean pulmonary arterial pressure (P̄pa) ≥25 mmHg and severe PH as a P̄pa >40 mmHg. Independent factors associated with PH were determined. Of the 3,457 persons listed, 2,525 (73.0%) had undergone RHC. PH affected 46.1% of subjects; ∼9% had severe PH. Variables independently associated with mild-to-moderate PH were as follows: need for oxygen, pulmonary capillary wedge pressure (Ppcw) and forced expiratory volume in one second (FEV1). Independent factors related to severe PH included the following: carbon dioxide tension, age, FEV1, Ppcw, need for oxygen and ethnicity. A sensitivity analysis in subjects with Ppcw <15 mmHg did not appreciably alter the present findings. Pulmonary hypertension is common in idiopathic pulmonary fibrosis patients awaiting lung transplant, but the elevations in mean pulmonary arterial pressure are moderate. Lung volumes alone do not explain the pulmonary hypertension. Given the prevalence of pulmonary hypertension and its relationship with surrogate markers for quality of life (e.g. activities of daily living), future trials of therapies for this may be warranted.

Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics

Pulmonary hypertension (PH) is a predictor of poor outcome in sarcoidosis. Little is known about the epidemiology of PH in sarcoidosis. The current authors reviewed the records of patients with sarcoidosis listed for lung transplantation in the USA between January 1995 and December 2002. PH was defined as a mean pulmonary artery pressure of >25 mmHg and severe PH as a mean pulmonary artery pressure of ≥40 mmHg. The cohort included 363 patients of whom 73.8% had PH. Neither spirometric testing nor the need for corticosteroids was associated with PH. Subjects with PH required more supplemental oxygen (2.7±1.8 L·min−1 versus 1.6±1.4 L·min−1). The cardiac index was lower in individuals with PH, whereas the pulmonary capillary wedge pressure was higher. In multivariate analysis, supplemental oxygen remained an independent predictor of PH, whereas the relationship between cardiac index and PH was no longer significant. As a screening test, the need for oxygen had a sensitivity and specificity of 91.8% and 32.6%, respectively. Pulmonary hypertension is common in advanced sarcoidosis. The need for oxygen correlates with pulmonary hypertension. Since pulmonary hypertension is associated with poor outcomes and because simple clinical criteria fail to identify patients with sarcoidosis and pulmonary hypertension, more aggressive screening for this should be considered.

Treatment of idiopathic pulmonary fibrosis with ambrisentan: a randomized trial

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.BACKGROUND Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING Academic and private hospitals. PARTICIPANTS Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION The study was terminated early. CONCLUSION Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE Gilead Sciences.

Pulmonary Hypertension and Pulmonary Function Testing in Idiopathic Pulmonary Fibrosis

BACKGROUND Pulmonary hypertension (PH) is commonly seen in patients with idiopathic pulmonary fibrosis (IPF). We sought to examine the relationship between pulmonary function tests (PFTs), including the percentage of predicted FVC (FVC%), percentage of predicted total lung capacity, percentage of predicted diffusing capacity of the lung for carbon monoxide (Dlco%), the composite physiologic index (CPI), and PH. The ability of FVC%, Dlco%, and FVC%/Dlco% ratio to predict underlying PH was assessed. METHODS Retrospective review of IPF patients seen at a tertiary referral center over an 8-year interval in whom both PFT and right-heart catheterization data were available. RESULTS The study cohort consisted of 118 patients, of whom 48 patients (40.7%) had PH. There was no correlation between measures of lung volumes or the CPI with underlying PH. There was a modest association between Dlco% and PH, with Dlco% < 30 having a twofold-higher prevalence of PH (56.4%) compared to Dlco% >/= 30 (28.6%). Cardiac dysfunction might have played a small role, since 16.1% of the patients had an associated elevated pulmonary capillary wedge pressure. There was a trend to a higher prevalence and greater severity of PH in those patients with FVC% > 70 compared to the group with FVC% < 40. CONCLUSION PH is common in patients with IPF. There is a poor correlation between lung function measures and PH, suggesting that factors other than fibrosis may play a role in the etiology. The unexpected high prevalence and severity of PH in patients with well-maintained lung function have implications for the prognosis and management of the disease.

Long-term Course and Prognosis of Idiopathic Pulmonary Fibrosis in the New Millennium

The American Thoracic Society and European Respiratory Society guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) have been published recently. However, the influence, practical application, and utility of the prior consensus statement for IPF have never been evaluated. Demographics, diagnostic criteria, pulmonary function data, and disposition of patients with IPF evaluated at an interstitial lung disease center between 2000 and 2009 were analyzed. Enrollment in clinical drug trials, lung transplantation, and mortality also were assessed. A total of 521 patients with IPF were evaluated, with pulmonary function testing available in 446. In the 64% of patients without surgical lung biopsy, the most common major criterion not fulfilled was bronchoscopy. Lung transplantation was performed in 16.1% of patients, whereas 27.4% of prescreened patients were enrolled in a prospective drug study. Patients with mild, moderate, and severe disease categorized by FVC % predicted had median survivals of 55.6, 38.7, and 27.4 months, respectively. The attrition rate of patients who survived beyond 5 years was attenuated in subsequent years. IPF remains a deadly disease with a poor prognosis. Bronchoscopy does not appear to be required for an accurate diagnosis. A minority of patients were accommodated within a clinical trial or with transplantation. Categorization by baseline FVC % predicted effectively discriminates groups with different long-term outcomes. Our analysis supports the view that the value of statements also can be realized in the subsequent demonstration of their impact on patient management, which might enable further refinements in a continuous, iterative rediscovery process.

Predicting mortality in patients with sarcoidosis awaiting lung transplantation.

OBJECTIVES To identify factors associated with mortality in patients with sarcoidosis listed for lung transplantation, and to create a model for predicting intermediate-term mortality in these individuals. DESIGN Retrospective cohort study of patients with sarcoidosis listed for lung transplant in the United States between 1995 and 2000. After identifying important risk factors for death, we developed a mortality prediction model based on an inception cohort of 75% of the subjects. The remaining 25% of the individuals served as a validation cohort for determining the validity of the model. SETTING AND PATIENTS All patients with sarcoidosis in the United States irrespective of referral center listed for lung transplantation between 1995 and 2000. MEASUREMENTS AND MAIN RESULTS Adequate follow-up data were available for 405 patients, and 111 patients (27.4%) died while awaiting lung transplantation. Neither patient age nor gender correlated with mortality. Survivors and nonsurvivors did not differ based on the results of spirometric testing. African Americans faced a significantly increased risk of death, which persisted after controlling for other confounders (odds ratio, 2.5). The amount of supplemental oxygen used and the mean pulmonary artery pressure were the only other variables predictive of mortality. The mean (+/- SD) pulmonary artery pressure in those who survived was 31.7 +/- 11.5 mm Hg, compared to 41.4 +/- 14.4 mm Hg in nonsurvivors (p < 0.01). Survivors required 2.2 +/- 2.0 L/min of oxygen vs 2.9 +/- 1.7 L/min in those who died awaiting transplant (p < 0.01). Differences in pulmonary artery pressures did not reflect differences in cardiac status, as the pulmonary capillary wedge pressure and the cardiac index were similar in survivors and nonsurvivors. The final mortality prediction model included three variables: race, amount of supplemental oxygen needed, and mean pulmonary artery pressure. Based on the validation cohort, the concordance of the model for death within 2 years of listing was 0.61 (95% confidence interval, 0.47 to 0.76), indicating only moderate explanatory power. CONCLUSIONS Race, pulmonary hypertension, and oxygen use are important factors indicative of mortality in this population. Specific guidelines for determining time of referral for transplantation in advanced sarcoidosis should be developed. Recommendations extrapolated from data for other types of interstitial lung disease may not be applicable in sarcoidosis. The independent effect of race on outcome is troubling.

Serial Development of Pulmonary Hypertension in Patients with Idiopathic Pulmonary Fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with very high mortality. Objective: We sought to characterize serial changes in pulmonary artery pressures (PAP) in patients with advanced IPF who survive to transplant. Methods: Retrospective analysis of IPF patients comparing mean PAP at the time of initial evaluation for transplan- tation (mPAPbaseline) with mPAP at the time of transplant (mPAPfollow-up). The measurements were correlated with New York Heart Association (NYHA) functional class and oxygen requirements. Results: The final cohort consisted of 44 patients with serial right heart catheterization data. The mean mPAPbaseline and mPAPfollow-up were 22.5 and 32.7 mm Hg, respectively. 38.6% (17/44) of the patients had pulmonary hypertension (PH) at baseline. The majority of the non-PH patients developed PH during the serial time interval with a subsequent incidence of 77.8%. At the time of transplant, 86.4% of the patients had PH. There was a significant association between transplant NYHA class, severity of PH and oxygen requirements. Transplant NYHA class IV patients had a higher rate of mPAP change. The severity of PH at the time of transplant did not affect transplant outcomes. Conclusion: PH is common and progressive in patients with advanced IPF who are transplant candidates. Serial change and severity of PAP elevations have a significant association with oxygen requirements and functional status, but not transplant outcomes. Whether or not progressive PH has a significant impact on outcomes without transplantation requires further study.

Pirfenidone for idiopathic pulmonary fibrosis: Analysis of pooled data from three multinational phase 3 trials

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression. All patients randomised to pirfenidone 2403 mg·day−1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol. A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation. Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF. Treatment with pirfenidone for 1 year results in clinically meaningful reductions in IPF disease progression http://ow.ly/StvBk