Effect of transition from sitaxsentan to ambrisentan in pulmonary arterial hypertension

Zeenat SafdarDivision of Pulmonary-Critical Care Medicine, Baylor College of Medicine, Houston, Texas, USAIntroduction: Currently available endothelin receptor antagonists for treating pulmonary arterial hypertension block either the endothelin (ET) receptor A or both A and B receptors. Transition from one endothelin receptor antagonist to another may theoretically alter side-effects or efficacy. We report our experience of a transition from sitaxsentan to ambrisentan, both predominant ETA receptor antagonists, in pulmonary arterial hypertension patients.Methods: At Baylor Pulmonary Hypertension Center, 18 patients enrolled in the open-label extension phase of the original sitaxsentan studies (Sitaxsentan To Relieve ImpaireD Exercise) were transitioned to ambrisentan (from July 2007 to September 2007) at the time of study closure. Pre-transition (PreT), 1 month (1Mth) and 1 year (1Yr) post-transition assessments of 6-minute walk distance (6MWD), brain naturetic peptide (BNP) levels, WHO functional class (WHO FC), Borg dyspnea score (BDS), oxygen saturation, liver function, and peripheral edema were compared.Results: 6MWD was 356 ± 126 m at PreT, 361 ± 125 m at 1Mth, and 394 ± 114 m at 1Yr (mean ± SD). There was no difference in the walk distance at 1Mth and 1Yr post transition compared with PreT (P = 0.92, 0.41 respectively). Oxygen saturation was no different at 1Mth and 1Yr to PreT level (P = 0.49 and P = 0.06 respectively). BNP was 178 ± 244 pg/mL at PreT, 129 ± 144 pg/mL at 1Mth and 157 ± 201 at 1Yr. Peripheral edema was present in 7/18 patients at PreT, in 8/16 patients at 1Mth, and in 6/13 patients at 1Yr post transition. Proportions of patients with edema over these 3 time points did not change significantly (P = 0.803). At 1Yr, 2 patients had died, 1 had undergone lung transplantation, 1 had relocated, and 1 patient was started on intravenous prostacyclin therapy. Over 3 points (baseline, 1 month, and 1 year), there was no significant change in function class (P = 0.672).Conclusion: Our limited data suggest that ETA receptor antagonists can be switched from one to another with sustained exercise capacity and maintained WHO FC with no increase in incidence of peripheral edema.Keywords: right heart failure, 6-minute walk distance, endothelial receptor antagonist, echocardiogra

The predictors of outcome in immunocompetent patients with hematogenous candidasis

AbstractObjective: Clinical parameters that predict outcome in non-immunosuppressed candidemic patients are not fully understood.Methods: Eighty-one consecutive episodes of candidemia were retrospectively evaluated in 75 patients during 1998–2000.Results: Infection due to Candida albicans was common (n=30; 37%) followed by Candida glabrata (n=25; 31%), Candida parapsilosis (n=14; 17%), Candida tropicalis (n=6; 7%), Candida krusei (n=5; 6%), and Candida lusitaniae (n=1; 1%). Among 70 evaluable patients, 31 (44%) had fungemia-associated mortality; advanced age (P<0.004), underlying malignancy (P<0.025), coronary artery disease (P<0.01), and concurrent non-Candida species fungal infection (P<0.047) were significant prognosticators of compromised short-term survival by multivariate analysis. Mortality was higher in patients with Candida glabrata (60%) and C. tropicalis (75%) infection compared to 44% deaths in individuals with C. albicans infection (P>0.1). 11/25 (44%) of non-immunocompromised individuals died and 20/45 (44%) immunosuppressed patients succumbed to fungemia: persistent vs. non-persistent (<3 days) Candida bloodstream invasion, neutropenia, diabetes mellitus, renal insufficiency, prior antimicrobial therapy, cirrhosis of liver, abdomino-pelvis surgery, and critical-care-unit vs. non critical-care-unit admission did not significantly impact outcome in either group. All 11 infants, including nine with prematurity survived Candida species bloodstream infection (P<0.025).Conclusions: Short-term mortality in candidemic non-immunocompromised patients was comparable to fungemia-associated deaths in immunosuppressed patients. Ischemic heart disease has appeared as a new predictor of unfavorable outcome in patients with hematogenous candidiasis

Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat

Dual combination therapy with a phosphodiesterase‐5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate‐risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open‐ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from −5 (strongly disagree) to +5 (strongly agree) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus‐based recommendations may be helpful to clinicians and beneficial for patients when evidence‐based guidance is unavailable

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Abstract: Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions: Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants

Pulmonary arterial hypertension in pregnant women

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling that limits the ability of the pulmonary vascular bed to withstand the physiological changes of pregnancy. Historically, pregnancy in PAH carries a high risk to the parturient. Normal pulmonary vasculature can withstand the hemodynamic and physiological changes associated with pregnancy without the development of respiratory symptomatology. However, in the presence of pulmonary vascular remodeling the capacity to handle these changes is compromised. During pregnancy, increase in cardiac output from the increased intravascular volume can lead to right heart failure. Therefore, all patients with PAH of childbearing potential should receive preconception counseling and be advised to use two methods of contraception. Patients with PAH should be advised against continuing pregnancy if they do become pregnant. According to the literature, deterioration in pregnancy mainly occurs in the second trimester and early in the third trimester; immediately postpartum is the most critical time for patients with PAH. In this review, we will discuss the recent advances in the management of parturient patients with PAH

Goiter in a Patient with Pulmonary Arterial Hypertension Treated with Epoprostenol

A 35-year-old female with pulmonary arterial hypertension (PAH) who presented with complaints of progressively worsening dysphagia, facial swelling, and shortness of breath, was found to have a large goiter. In patients treated with epoprostenol for long periods of time, thyroid disease is common. Most cases of thyroid disease describe thyrotoxicosis and hyperthyroid statues, but our case was a patient on long term IV epoprostenol presenting with a superior vena cava-syndrome (SVC) like appearance and airway compromise found to have a goiter incidentally during workup

Update on pulmonary hypertension complicating chronic obstructive pulmonary disease

Soma Jyothula, Zeenat SafdarPulmonary-Critical Care Medicine, Baylor College of Medicine, Houston, TX, USAAbstract: Pulmonary hypertension (PH) is the hemodynamic manifestation of various pathological processes that result in elevated pulmonary artery pressures (PAP). The National Institutes of Health Registry defined pulmonary arterial hypertension as the mean PAP of more than 25 mm Hg with a pulmonary capillary wedge pressure or left atrial pressure equal to or less than 15 mm Hg. This definition remains the currently accepted definition of PH that is used to define PH related to multiple clinical conditions including chronic obstructive pulmonary disease (COPD). The estimated US prevalence of COPD by the National Health Survey in 2002 in people aged &amp;gt;25 was 12.1 million. There is a lack of large population-based studies in COPD to document the correct prevalence of PH and outcome. The major cause of PH in COPD is hypoxemia leading to vascular remodeling. Echocardiogram is the initial screening tool of choice for PH. This simple noninvasive test can provide an estimate of right ventricular systolic and right atrial pressures. Right heart catheterization remains the gold standard to diagnose PH. It provides accurate measurement of mean PAP and pulmonary capillary wedge pressure. Oxygen therapy remains the cornerstone therapeutic for hypoxemia in COPD patients. Anecdotal reports suggest utility of PDE5-inhibitors and prostacyclin to treat COPD-related PH. Large randomized clinical trials are needed before the use of these drugs can be recommended.Keywords: pulmonary arterial hypertension, airflow obstruction, vascular remodelin

Pulmonary hypertension complicated by pericardial effusion: a single center experience

Background: Pericardial effusion is an independent predictor of mortality in patients with pulmonary arterial hypertension (PAH). However, the management and outcomes of patients with pulmonary hypertension (PH) and pericardial effusion are not well described. Methods: A retrospective, observational study was conducted at Baylor College of Medicine and The Methodist Hospital by screening all patients admitted between 1 June 2005 and 1 June 2010 with the International Classification of Diseases, ninth revision codes for PH and pericardial effusion. A total of 138 patients were identified, and 103 patients were excluded on the basis of valvular heart disease, recent surgery or end-stage renal disease. Thirty-five patients with PH diagnosed by a historical right heart catheterization or echocardiography and with documented pericardial effusion were included in this analysis. Demographic, hemodynamic, laboratory and survival data were collected. Results: The mean age was 49.5±36 years (mean ± standard deviation), 31 of 35 patients were women (93%) and pulmonary artery systolic pressure was 77 ± 19 mmHg. Mean follow-up period was 20.5 ± 12.9 months. Fifteen patients had PAH associated with connective tissue disease (50%). The majority of the patients (87%) with pericardial effusion were managed conservatively. Four patients (13%) who were hemodynamically unstable underwent pericardial window placement. One of them was started on epoprostenol, and two patients had the doses of PAH-specific medications uptitrated. Three of four pericardial window patients survived to the conclusion of the follow-up period. The overall survival in our cohort was 60%, with three patients lost to follow-up. Conclusions: Connective tissue disease associated PAH and female sex were predominant in our cohort of patients with pericardial effusion. Seventy-five percent of patients who were treated with pericardial window for hemodynamically unstable pericardial effusion survived until the end of the study period. Pericardial window may be a therapeutic option in patients with unstable PH with pericardial effusion. Further studies are needed to determine the optimal treatment strategy for such patients

Pulmonary artery diastolic pressure gradient as an indicator of severity of illness in patients with pulmonary hypertension related to left-sided heart disease

Introduction: Pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is most commonly due to passive backward transmission of elevated left-sided heart pressures. A subgroup of these patients develop pulmonary artery remodeling, resulting in systolic and mean pulmonary artery pressures that are ‘reactive’ or ‘out of proportion’ to the elevated left-sided heart pressures. These patients have historically been identified by a transpulmonary gradient (TPG) > 12 mmHg. However, since diastolic pulmonary artery pressures are less susceptible to changes in pulmonary blood flow, a diastolic pulmonary gradient (DPG) ⩾ 7 mmHg may be a superior indicator of worse clinical function and prognosis. Methods: Based on measurements from a right-heart catheterization (RHC) database (Baylor College of Medicine, Houston, TX, USA), comparisons of several clinical parameters were made among three Group 2 PH patients: normal TPG and DPG (Group 2A), elevated TPG and normal DPG (Group 2B), and elevated TPG and DPG (Group 2C). Results: Among 173 RHCs, 39 were found to have Group 2 PH. Among these 39 cases, 10 (32%), 13 (32%), and 16 (36%) cases were categorized into Groups 2A, 2B, and 2C, respectively. Group 2C patients had significantly worse 6-min walk distance (308 ± 69 m) than Group 2A (425 ± 81 m) and Group 2B (350 ± 103 m) ( p = 0.038). There was no significant difference in cardiac output, cardiac index, and right atrial pressure among the three subgroups. Discussion: Among patients with Group 2 PH, elevated DPG proved to be a more specific indicator of worse functional status than the historically used TPG. International guidelines and protocols for performing RHC for the assessment and diagnosis of PH should include the measurement of DPG