Time To Clinical Worsening Research Articles

Low nailfold capillary density in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: biomarker of clinical outcome?

Nailfold capillary density is lower in patients with pulmonary arterial hypertension (PAH). It is unclear whether this observation signifies a unique systemic manifestation of PAH, or reflects microcirculatory dysfunction secondary to pulmonary hypertension (PH). Capillary density and loop dimensions were measured by nailfold-capillaroscopy (NC) in 30 PAH (23 idiopathic, or iPAH, 7 hereditary, or hPAH), 17 chronic thromboembolic PH (CTEPH) patients and 48 controls. NC-Measurements were repeated after pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) in CTEPH patients. We examined whether NC-measurements were related to markers of disease severity and predictive of time to clinical worsening (TTCW) as tested by univariate linear/logistic regression and cox-regression analysis, respectively. Capillary density was significantly lower in PAH (7.5 ± 1.1, p < 0.001) and in CTEPH (8.4 ± 1.5, p < 0.001) compared to asymptomatic controls (10.3 ± 1.0 capillaries/mm). Capillary density was similar in iPAH and hPAH and unrelated to hemodynamics in either PAH or CTEPH. A lower capillary density was predictive of clinical worsening in PAH (p 0.05). After normalization of pulmonary artery pressures by PEA or BPA, capillary density remained reduced in CTEPH patients. Capillary loop apex, capillary and venous- and arterial limb diameter were increased in patients with PAH and CTEPH compared to controls. Nailfold capillary density is reduced to a similar extent in iPAH, hPAH and CTEPH. Normalization of hemodynamics by PEA or BPA does not lead to a restoration of capillary density in CTEPH. Capillary dimensions were increased in both patients with PAH and CTEPH. Lower capillary density was predictive of clinical worsening in PAH. Our findings indicate that a loss of peripheral capillaries is not specific to PAH and is not related to the hemodynamic disturbance per se, but that shared mechanisms may account for a simultaneous development of a systemic microangiopathy and pulmonary vascular remodeling.

Risk assessment tools for survival prognosis: An era of new surrogacy endpoints for clinical outcome measurement in pulmonary arterial hypertension clinical trials?

Developing a new medication in a rare disease indication like pulmonary arterial hypertension (PAH) is very challenging. This is especially true now that clinical trials often employ time to clinical worsening (TTCW) as an endpoint (thus requiring a relatively large and lengthy trial) and since patients are more frequently prescribed combination therapy. During the last few decades, several tools have been developed to predict mortality in PAH and have demonstrated generally good discrimination. The objective of this review article is to assess the available data on the different tools and methods described in the literature and identify potential candidates that could be used as surrogate endpoints in pivotal randomized clinical trials in future. Some of these tools have been validated in various registries and in post-hoc analyses of clinical trial data, but none have been assessed in a prospective clinical trial and we still lack the evidence necessary for endorsement by health authorities. In this review, we identify several promising options that warrant further investigation as potential surrogate endpoints in clinical trials to replace TTCW or 6-minute walk distance. Prospective inclusion of such tools in new clinical trials may help build a stronger surrogacy for prognosis of disease progression and mortality.

The Association of N-Terminal Pro-Brain Natriuretic Peptide With Time to Clinical Worsening in Hispanic Patients With Pulmonary Arterial Hypertension.

BackgroundMeasurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) level is an important parameter in the risk assessment of patients with pulmonary arterial hypertension (PAH). Data about the prognostic value of NT-proBNP in the Hispanic PAH population are lacking. Historically, clinical trials in PAH have only included a minority of Hispanic patients. It has been reported that baseline NT-proBNP levels differ between different ethnicities. Furthermore, NT-proBNP levels can be impacted by declining renal function, making its interpretation difficult regarding clinical decision making.MethodsIn a retrospective single-center cohort analysis, Hispanic patients with PAH had a baseline outpatient NT-proBNP level drawn during a period of clinical stability and were followed for 1 year to monitor for time to clinical worsening (TTCW). The association of baseline NT-proBNP and TTCW was assessed in patients with normal and abnormal renal function.ResultsA total of 26 patients (22%) met the clinical endpoint of clinical worsening. Twenty-seven patients (24%) had chronic kidney disease (CKD). At baseline NT-proBNP levels showed a significant inverse correlation with 6-min walk test (6MWD, r = -0.382, P = 0.02), and a significant positive correlation with renal function (r = 0.273, P = 0.05). NT-proBNP levels did not correlate with age (r = 0.19, P = 0.11) or body mass index (BMI) (r = -0.292, P = 0.061). NT-proBNP levels of > 1,415 ng/L were significantly associated with shorter TTCW (P < 0.01) in all patients and in patients with CKD (P = 0.03). A stepwise increase in NT-proBNP levels by 100 ng/L was associated with a higher risk of meeting the clinical endpoint of TTCW in patients with normal renal function (hazard ratio (HR) = 1.8, P < 0.01) and CKD (HR = 1.5, P < 0.01).ConclusionsIn Hispanic patients with PAH, NT-proBNP is a valuable tool to predict 1-year TTCW, independent of renal function.

Prognostic impact of hypochromic erythrocytes in patients with pulmonary arterial hypertension

BackgroundIron deficiency affects up to 50% of patients with pulmonary arterial hypertension (PAH) but iron markers such as ferritin and serum iron are confounded by several non-disease related factors like acute inflammation and diet. The aim of this study was to identify a new marker for iron deficiency and clinical outcome in PAH patients.MethodsIn this single-center, retrospective study we assessed indicators of iron status and clinical parameters specifying the time to clinical worsening (TTCW) and survival in PAH patients at time of initial diagnosis and at 1-year follow-up using univariable and multivariable analysis.ResultsIn total, 150 patients were included with an invasively confirmed PAH and complete data on iron metabolism. The proportion of hypochromic erythrocytes > 2% at initial diagnosis was identified as an independent predictor for a shorter TTCW (p = 0.0001) and worse survival (p = 0.002) at initial diagnosis as well as worse survival (p = 0.016) at 1-year follow-up. Only a subset of these patients (64%) suffered from iron deficiency. Low ferritin or low serum iron neither correlated with TTCW nor survival. Severe hemoglobin deficiency at baseline was significantly associated with a shorter TTCW (p = 0.001).ConclusionsThe presence of hypochromic erythrocytes > 2% was a strong and independent predictor of mortality and shorter TTCW in this cohort of PAH patients. Thus, it can serve as a valuable indicator of iron homeostasis and prognosis even in patients without iron deficiency or anemia. Further studies are needed to confirm the results and to investigate therapeutic implications.

Riociguat for Sarcoidosis-Associated Pulmonary Hypertension: Results of a 1-Year Double-Blind, Placebo-Controlled Trial

Riociguat is effective in delaying the time to clinical worsening (TCW) in patients with groups 1 and 4 pulmonary hypertension. Is riociguat more effective than placebo in prolonging TCW in sarcoidosis-associated pulmonary hypertension (SAPH)? This was a double-blind placebo-controlled trial. Patients with SAPH confirmed by right heart catheterization were randomized 1:1 to riociguat or placebo. Patients underwent 6-min walk distance (6MWD) and spirometry testing every 8weeks. The primary end point was TCW, which was defined by the time to the first of the following: (1) all-cause mortality, (2) need for hospitalization because of worsening cardiopulmonary status attributable to progression of disease, (3) > 50m decrease in the 6MWD test, or (4) worsening of World Health Organization functional class. A total of 16 patients were randomized to riociguat (n= 8) or placebo (n= 8). No difference was found in pulmonary artery mean, pulmonary vascular resistance, initial 6MWD, or FVC between the two groups. Five of eight patients who received placebo met TCW criteria, whereas none of the patients who received riociguat experienced a qualifying event. By log-rank analysis, patients who received riociguat were in the study for a significantly longer period (χ 2= 6.259; P= .0124). The 6MWD decreased in the placebo group (median, -55.9 m; range, -176.8 to 60 m), but rose in the riociguat group (median,+42.7 m; range, -7.5 to+91.4 m; P= .0149), with a placebo-corrected difference of 94m (P< .01). Four of eight patients who received riociguat, but only 1 of 8 patients who received placebo, showed a > 30-m improvement in 6MWD (P > .05). No significant adverse events associated with riociguat occurred. Over the 1 year of the study, riociguat was effective in preventing clinical worsening and improving exercise capacity in patients with SAPH. ClinicalTrials.gov; No.: NCT02625558; URL: www.clinicaltrials.gov.

Using Real-World Data to Optimize Strategic Planning for Pulmonary Arterial Hypertension Clinical Trials

Introduction Pulmonary arterial hypertension (PAH) clinical trials are evolving from small, surrogate endpoint studies based primarily in North America (NA) and Western Europe (WE), to larger, clinical endpoint trials with investigative sites around the world. Limited clinical trial experience with PAH beyond NA and WE presents a challenge to planning key elements of a study such as determining country and site selection and predicting event rates. We sought to develop a data-driven approach to estimate event rates and optimize strategic planning for PAH clinical trials. Methods We used the IMS prescription database, which includes prescription data from hospital, retail, mail service, and long-term care pharmacies in over 90 countries. We reviewed global prescription data to characterize the use of cornerstone PAH therapies in various countries as days of treatment per population count. We used this information to determine which countries had a higher use of PAH drugs and where combination therapy vs. monotherapy was most likely to be used. We reviewed previous PAH clinical trials to estimate time to clinical worsening (TTCW) rates for patients receiving monotherapy (∼25-30% events/yr.) vs. combination therapy (∼15-20% events/yr.). Results Regions and countries with the highest consumption of PAH specific drugs were NA, WE, and Japan ( Figure ). The lowest use of PAH specific drugs was in Latin America (LA). Endothelin receptor antagonists (ERAs) were used in countries throughout NA, WE, Eastern Europe (EE), and Asia. Use of newer therapies occurred only in select regions: riociguat, a soluble guanylate cyclase stimulator, was used mostly in WE, EE, Canada, Japan, and Taiwan, and selexipag, a prostacyclin receptor agonist, was used mostly in NA, WE, and Japan. Conclusions Our analysis showed that greater use of PAH specific drugs occurred in higher income regions such as NA, WE, and Japan; therefore, we predicted greater use of combination PAH therapy in these areas. There was lower use of PAH specific drugs in EE, LA, and Asia; thus, we predicted a higher prevalence of monotherapy in these regions. Understanding global prescription patterns and associated estimated event rates may allow for a more data-driven approach to developing enrollment timelines and selecting countries and sites for PAH clinical trials.

Clinical and hemodynamic improvements after adding ambrisentan to background PDE5i therapy in patients with pulmonary arterial hypertension exhibiting a suboptimal therapeutic response (ATHENA-1)

ObjectivePulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and premature death. While recent data supports the initial combination of ambrisentan (a selective ERA) and tadalafil (a PDE5i) in functional class II or III patients, there is no published data describing the safety and efficacy of ambrisentan when added to patients currently receiving a PDE5i and exhibiting a suboptimal response. The ATHENA-1 study describes the safety and efficacy of the addition of ambrisentan in this patient population. MethodsPAH patients with a suboptimal response to current PDE5i monotherapy were assigned ambrisentan in an open-label fashion and evaluated for up to 48 weeks. Cardiopulmonary hemodynamics (change in PVR as primary endpoint) were evaluated at week 24 and functional parameters and biomarkers were measured through week 48. Time to clinical worsening (TTCW) and survival are also described. ResultsThirty-three subjects were included in the analysis. At week 24, statistically significant improvements in PVR (−32%), mPAP (−11%), and CI (+25%) were observed. Hemodynamic improvements at week 24 were further supported by improvements in the secondary endpoints: 6-min walk distance (+18 m), NT-proBNP (−31%), and maintenance or improvement in WHO FC in 97% of patients. Adverse events were consistent with known effects of ambrisentan. ConclusionThe hemodynamic, functional, and biomarker improvements observed in the ATHENA-1 study suggests that the sequential addition of ambrisentan to patients not having a satisfactory response to established PDE5i monotherapy is a reasonable option.

Sex and menopause differences in response to tadalafil: 6-minute walk distance and time to clinical worsening.

Pulmonary arterial hypertension (PAH) is a female-predominant disease, but there are little data on treatment response by sex and menopausal status. In this retrospective analysis of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) randomized clinical trial, we assessed treatment response between the sexes by examining change in 6-minute walk distance (6MWD) and time to clinical worsening (TCW). We examined the effect of menopausal status on the same treatment measures. 6MWD was recorded before and after 16 weeks of treatment with tadalafil or placebo in the PHIRST study cohort of 340 subjects (264 females, 76 males). A univariate analysis was used to assess the effect of sex on change in 6MWD and TCW. Multivariate linear regression and Cox proportional hazards models were built for 6MWD and TCW, respectively. Women were subdivided by age as a surrogate for menopausal status. The linear trend test and the log-rank test were performed on change in 6MWD and TCW by age. For tadalafil-treated patients, a significant difference in change in 6MWD by sex (mean: 48.6 m for males vs. 34.7 m for females; P = 0.01) was found, but it was not significant in multivariate analysis (P = 0.08). There was a trend toward a female age-dependent effect in change in 6MWD; the premenopausal group showed the greatest improvement. A significant sex- or age-dependent effect on TCW was not present. In conclusion, this retrospective analysis of the PHIRST trial suggests that men and premenopausal women may experience greater functional improvement when treated with tadalafil than older women, but there was no consistent sex or menopausal effect on TCW.

Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: Clinical associations

Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival. In the 18-week, double-blind, placebo-controlled STRIDE-2 trial, 246 PAH patients were randomized and received matched placebo, sitaxentan 50 or 100 mg orally once daily, or open-label bosentan 125 mg twice daily. STRIDE-2X was a 1-year, open-label extension of STRIDE-2. Baseline serum uric acid was similar between groups. Increased serum uric acid was a significant risk factor for 1-year mortality and TtCW. Compared with placebo, sitaxentan 50 and 100 mg and bosentan all reduced serum uric acid (p < 0.05). Reduced serum uric acid correlated with increased 6MWD (p = 0.0037). Endothelin receptor antagonism reduces serum uric acid in PAH patients, and this reduction is associated with improved survival and longer TtCW. Further prospective studies are needed to investigate the pathogenic role of serum uric acid in PAH and its prognostic potential.

Updating Clinical Endpoints in Pulmonary Arterial Hypertension: When Challenges are Welcome

We thank Ms. Deborah McCollister for her feedback on our recent article titled “Updating clinical endpoint definitions.” McCollister judiciously points out some of the challenges raised with the recent trend among investigators and pharmaceutical companies involved in pulmonary arterial hypertension (PAH) clinical trials to move away from the 6‐minute walk distance (6MWD) as a primary outcome in favor of a more composite endpoint, such as time to clinical worsening (TTCW), which includes elements of morbidity (such as hospitalization, clinical worsening, and need for additional therapy) and mortality.

Gender Differences in Response to PAH Therapy: 6MWD and Time to Clinical Worsening

Purpose Pulmonary Arterial Hypertension is a female predominant disease but there is little data on therapy response by gender. 1 We assessed treatment response in males vs females by examining change in six-minute walk distance (6MWD) and time to clinical worsening (TCW). We also investigated the effects of menopause on treatment response using age as a predictor of menopausal status. 1. Shapiro S, et al. REVEAL. Chest. 2011;10-3114. Methods and Materials 6MWD was recorded before and after 16 weeks of treatment in the PHIRST study in a cohort of 340 subjects (264 F and 76 M), among a total of 405 subjects (317 F and 88 M). 2 Wilcoxon Rank sum test was used to assess gender effect on change in 6MWD and Log-rank test was used to assess gender effect on TCW. The females were subdivided by age to estimate menopausal status: 14-44 yrs premenopausal, 45-55yrs perimenopausal and ≥56yrs postmenopausal. Log-rank test was performed on TCW by age among females. 2.Galie N, et al. Tadalafil Therapy for PH. Circulation. 2009;10.1161. Results A statistically significant difference in change in 6MWD among males vs females (Median: 51.5 m vs. 26.5 m; p=0.008) was found. Log-rank test, however, did not show a consistent gender effect on TCW. There was a trend for a female age-dependent effect in change in 6MWD; the premenopausal group showed the greatest improvement, followed by peri- and postmenopausal. However, Log-rank test did not show a consistent age group effect on TCW. Conclusions Overall these analyses indicate a need for further investigation of the effects of gender and menopause on treatment response. Despite significant differences between the genders in 6MWD there was no consistent gender effect on TCW. It is possible that a smaller change in 6MWD may be tolerated in females. Given the suggested trend for more progressive worsening in postmenopausal females, a longitudinal study may be helpful to characterize this trend. Future work might explore the correlation between 6MWD and TCW in women.

Exercise testing to predict outcome in idiopathicversusassociated pulmonary arterial hypertension

We tested the ability of exercise testing to predict not only survival, but also time to clinical worsening (TTCW) in idiopathic versus associated pulmonary arterial hypertension (PAH). 136 patients with PAH (85 idiopathic and 51 with associated conditions) underwent cardiopulmonary exercise testing and a 6-min walk test. Death or transplantation, and clinical worsening events were recorded. 32 patients died and four had lung transplantation. In a univariate analysis, PAH patients survival was associated with oxygen uptake (V'(O(2))) at peak exercise and at the anaerobic threshold, ventilatory equivalent for carbon dioxide (minute ventilation (V'(E))/carbon dioxide production (V'(CO(2))) at the anaerobic threshold ((at))), V'(E)/V'(CO(2)) slope and distance walked. TTCW was associated with peak V'(O(2)) and V'(O(2),at), V'(E)/V'(CO(2),at), end-tidal carbon dioxide tension measured at the anaerobic threshold, peak oxygen pulse, increase in oxygen pulse and distance walked. In a multivariable analysis, distance walked and V'(E)/V'(CO(2),at) predicted survival, and only peak V'(O(2)) predicted TTCW. The receiver operating characteristic curve-derived cut-off values were 305 m for the 6-min walk distance, 54 for V'(E)/V'(CO(2),at) and 11.6 mL·kg(-1)·min for peak V'(O(2)). In the subgroup with associated PAH, no variable independently predicted either survival or clinical worsening. We conclude that several exercise variables predict survival and clinical stability in idiopathic PAH. Exercise variables are less accurate predictors of outcome in associated PAH.

Clinical Worsening During Long-Term Follow-Up in Inoperable Chronic Thromboembolic Pulmonary Hypertension

Pulmonary endarterectomy is the treatment of choice in chronic thromboembolic pulmonary hypertension (CTEPH). Modern pulmonary vasoactive medication (like endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins) is used in patients with an inoperable disease and improved prognosis. We evaluate mortality and time to clinical worsening (TtCW) in inoperable CTEPH patients during long-term follow-up. All 32 patients with inoperable CTEPH were enrolled between June 2002 and January 2009. TtCW was defined as the combination of death, need for intravenous pulmonary arterial hypertension medication, or 15% decrease in 6-minute walk distance (6-MWD) without improvement in functional class. The Cox proportional hazard regression was used to identify predictors. During a mean follow-up of 3.4 years (range = 0.2-10.2 years), 11 patients died (34%). The 1- and 3-year survival rates were 87 and 77%, respectively. Baseline functional class, 6-MWD, mean pulmonary artery pressure, and pulmonary vascular resistance were predictors for survival. Clinical worsening occurred in 16 patients (50%). The 1- and 3-year rates of freedom from clinical worsening were 74 and 60%, respectively. The only predictor for clinical worsening was the baseline 6-MWD. Despite the improvement in medical treatment of inoperable CTEPH, the mortality rate is still high, and clinical worsening occurred in a substantial number of patients during a follow-up of more than 3 years.

Safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension

ObjectiveTo assess safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension (PAH). BackgroundSitaxsentan is a highly selective endothelin-A receptor antagonist that was recently withdrawn by the manufacturer because of a pattern of idiosyncratic liver injury. MethodsBefore sitaxsentan withdrawal, this 18-week double-blind, placebo-controlled study randomized patients with PAH to receive placebo or sitaxsentan 50 or 100 mg once daily. The primary efficacy endpoint was change from baseline in 6-min walk distance (6MWD) at week 18. Changes in World Health Organization (WHO) functional class and time to clinical worsening (TTCW) were secondary endpoints. The primary efficacy analysis was powered for sitaxsentan 100 mg versus placebo. ResultsOf 98 randomized patients, 61% were WHO functional class II at baseline. Improvement from baseline to week 18 in 6MWD occurred with sitaxsentan 100 but not 50 mg; a strong placebo effect was observed. At week 18, WHO functional class was improved or maintained in more patients receiving sitaxsentan 100 mg than placebo (P = 0.038); 0% versus 12% of patients deteriorated, respectively. TTCW was not significantly different for 100-mg sitaxsentan patients than placebo (P = 0.090). Adverse events (AEs) occurring more frequently with sitaxsentan (50 or 100 mg) included headache, peripheral edema, dizziness, nausea, extremity pain, and fatigue; most AEs were of mild or moderate severity. ConclusionSitaxsentan 100 mg improved functional class but not 6MWD in PAH patients who were mostly WHO functional class II at baseline. No patient receiving sitaxsentan 100 mg experienced clinical worsening; sitaxsentan was well tolerated.

Clinical worsening in trials of pulmonary arterial hypertension: results and implications

Time to clinical worsening (TTCW) can be used to assess disease progression associated with pulmonary arterial hypertension (PAH). As a consequence, it is highly relevant to patients, clinicians, and regulatory agencies. The majority of clinical trials of PAH-specific drug therapies have included TTCW as a secondary endpoint; this article summarizes the results of randomized controlled clinical trials in PAH, specifically with respect to the clinical worsening endpoint. Some trials have demonstrated a treatment-related delay in TTCW and others have not. Recent results suggest that TTCW shows particular promise in detecting disease progression, even in mildly affected patients. Definitions of clinical worsening have also varied across clinical trials; although all have agreed on the inclusion of all-cause death and hospitalization due to PAH in the definition, the inclusion of additional parameters defining 'disease progression' has differed. There is a need for a clear and uniform definition of TTCW that can be tailored to the study population being investigated; the endpoint may require adaptation for patients in different functional classes and with different causes. Consistency of event reporting within a trial may be improved by employing a committee to adjudicate events. Trials are beginning to include TTCW as a primary endpoint; the results will be important in establishing the validity of whether this parameter should become the endpoint of choice in PAH trials in the future.

Perspective on the optimal endpoints for pulmonary arterial hypertension trials

Traditional endpoints in trials of therapies for pulmonary arterial hypertension (PAH), including 6-min walk distance, are associated with significant limitations. Time to clinical worsening (TTCW) may represent an alternative, and although it is being considered as a primary endpoint in future trials, it will ultimately require refinement before it can be broadly applied. Discussions with regulators about TTCW are ongoing, and there are several potential strategies that could be applied to enhance its robustness. For example, reliability and reproducibility could be increased if each individual component of TTCW were carefully defined. The optimal definition of TTCW may need to be varied in order to meet the differing needs of factors that include PAH cause, functional class, and age. The establishment of an independent and blinded committee who adjudicate problematic events (e.g. PAH-related hospitalization) in PAH trials using TTCW would further increase reliability, reducing intersite and interinvestigator variability. As the field continues to develop, overall trial design may warrant attention; to make results more clinically relevant, goal-orientated therapy strategies may be considered, in addition to traditional randomized controlled trial designs.

92: Sitaxsentan improves time to clinical worsening (TCW) in patients with pulmonary arterial hypertension (PAH)

Sitaxsentan, an oral, once-daily, highly selective endothelin A receptor antagonist, has been studied in two previously reported pivotal, randomized, double-blind, placebo controlled PAH studies. Here, we report a combined analysis of TCW from both studies.