A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance

Kumudha Ramasubbu1, Anita Deswal1, Cheryl Herdejurgen2, David Aguilar1, Adaani E Frost21Section of Cardiology, Michael E DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas, USA; 2Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Texas, USABackground: Pulmonary hypertension (PH), a disease which carries substantial morbidity and mortality, has been reported to occur in 25%–45% of dialysis patients. No prospective evaluation of the prevalence or clinical significance of PH in chronic dialysis patients in the United States (US) has been undertaken.Methods: Echocardiograms were performed prospectively in chronic hemodialysis patients prior to dialysis at a single dialysis center. PH was defined as a tricuspid regurgitant jet ≥2.5 m/s and “more severe PH” as ≥3.0 m/s. Clinical outcomes recovered were all-cause hospitalizations and death at 12 months.Results: In a cohort of 90 patients, 42 patients (47%) met the definition of PH. Of those, 18 patients (20%) met the definition of more severe PH. At 12 months, mortality was significantly higher in patients with PH (26%) compared with patients without PH (6%). All-cause hospitalizations were similar in patients with PH and without PH. Echocardiographic findings suggesting impaired left ventricular function and elevated pulmonary capillary wedge pressure were significantly associated with PH.Conclusion: This prospective cross-sectional study of a single dialysis unit suggests that PH may be present in nearly half of US dialysis patients and when present is associated with increased mortality. Echocardiographic findings demonstrate an association between elevated filling pressures, elevated pulmonary artery pressures, and higher mortality, suggesting that the PH may be secondary to diastolic dysfunction and compounded by volume overload.Keywords: renal failure, pulmonary hypertension, diastolic dysfunctio

Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension

Background: Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. Methods: AMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to oncedaily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline. Results: This analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42 (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups. Conclusions: Treatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe

Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension‒related hospitalization in the AMBITION trial

Background: In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. Methods: The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. Results: Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). Conclusions: Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy

Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial

Background: The purpose of this study was to compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction. Methods: Treatment-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event. Results: Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g., hypertension and diabetes). Treatment effects of initial combination therapy vs pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35-0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35-1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients. Conclusions: Efficacy of initial combination therapy vs pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients

Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension With Oral Prostacyclin Pathway Agents

Background Treatment of pulmonary arterial hypertension (PAH) has evolved substantially over the past two decades and varies according to etiology, functional class (FC), hemodynamic parameters, and other clinical factors. Current guidelines do not provide definitive recommendations regarding the use of oral prostacyclin pathway agents (PPAs) in PAH. To provide guidance on the use of these agents, an expert panel was convened to develop consensus statements for the initiation of oral PPAs in adults with PAH. Methods A systematic literature search was conducted using MEDLINE. The established RAND/University of California Los Angeles appropriateness method, which incorporates the Delphi method and the nominal group technique, was used to create consensus statements. Idiopathic, heritable, repaired congenital heart defect, and drug- or toxin-induced PAH (IPAH+) was considered as one etiologic grouping. The process was focused on the use of oral treprostinil or selexipag in patients with IPAH+ or connective tissue disease-associated PAH and FC II or III symptoms receiving background dual endothelin receptor antagonist/phosphodiesterase type 5 inhibitor therapy. Results The panel developed 14 consensus statements regarding the appropriate use of oral PPAs in the target population. The panel identified 13 clinical scenarios in which selexipag may be considered as a treatment option. Conclusions The paucity of clinical evidence overall, and particularly from randomized trials in this setting, creates a gap in knowledge. These consensus statements are intended to aid physicians in navigating treatment options and using oral PPAs in the most appropriate manner in patients with PAH

Long-term safety and efficacy of imatinib in pulmonary arterial hypertension

Abstract BACKGROUND: Imatinib is an oral inhibitor of several protein kinases implicated in the pathophysiology of pulmonary hypertension. Treatment with imatinib resulted in improved hemodynamics and exercise capacity in a controlled trial (Imatinib [QTI571] in Pulmonary Arterial Hypertension, a Randomized Efficacy Study [IMPRES]), among pulmonary arterial hypertension (PAH) patients inadequately responsive to 2 to 3 PAH-specific therapies. METHODS: The long-term (up to 204 weeks) safety and efficacy of imatinib in this open-label extension study were reviewed until early study termination on April 16, 2014. Of 202 IMPRES-enrolled patients, 66 imatinib and 78 placebo recipients entered the extension. RESULTS: Overall, 93.8% (135 of 144) of patients discontinued the extension study; administrative issues (i.e., sponsor termination; 32.6%) and adverse events (31.3%) were the primary reasons for discontinuation. Nine patients completed the extension study before it was terminated. Serious and unexpected adverse events were frequent. These included 6 subdural hematomas in the extension study and 17 deaths during or within 30 days of study end. Although the patients who tolerated imatinib and remained in the extension for a longer duration did experience an improvement in functional class and walk distance, most discontinued the drug and the study. CONCLUSIONS: Severe adverse events, significant side effects, and a high discontinuation rate limit the utility of imatinib in the treatment of PAH. These risks outweigh any possible improvements in hemodynamics and walk distance seen in those patients able to remain on drug. The off-label use of this compound in PAH is discouraged

Optimization of Acute Kidney Injury (AKI) Time Definitions Using the Electronic Health Record: A First Step in Automating In-Hospital AKI Detection

Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney injury (AKI) definitions were evaluated for cases detected and their respective outcomes using expanded time windows to 168 h. AKI incidence and outcomes with expanded time intervals were identified in the electronic health records (EHRs) from 126,367 unique adult hospital admissions (2012–2014) and evaluated using multivariable logistic regression with bootstrap sampling. The incidence of AKI detected was 7.4% (n = 9357) using a 24-h time window for both serum creatinine (SCr) criterion 1a (≥0.30 mg/dL) and 1b (≥50%) increases from index SCr, with additional cases of AKI identified: 6963 from 24–48 h.; 2509 for criterion 1b from 48 h to 7 days; 3004 cases (expansion of criterion 1a and 1b from 48 to 168 h). Compared to patients without AKI, adjusted hospital days increased if AKI (criterion 1a and 1b) was observed using a 24-h observation window (5.5 days), 48-h expansion (3.4 days), 48-h to 7-day expansion (6.5 days), and 168-h expansion (3.9 days); all are p < 0.001. Similarly, the adjusted risk of in-hospital death increased if AKI was detected using a 24-h observation window (odds ratio (OR) = 16.9), 48-h expansion (OR = 5.5), 48-h to 7-day expansion (OR = 4.2), and 168-h expansion (OR = 1.6); all are p ≤ 0.01. Expanding the time windows for both AKI SCr criteria 1a and 1b standardizes and facilitates EHR AKI detection, while identifying additional clinically relevant cases of in-hospital AKI