Definitions and Diagnosis of Pulmonary Hypertension Hoeper, Marius M., MD; Bogaard, Harm Jan, MD; Condliffe, Robin, MD ...
Journal of the American College of Cardiology,
12/2013, Letnik:
62, Številka:
25
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest, measured during right heart catheterization. There is still insufficient evidence to add an exercise ...criterion to this definition. The term pulmonary arterial hypertension (PAH) describes a subpopulation of patients with PH characterized hemodynamically by the presence of pre-capillary PH including an end-expiratory pulmonary artery wedge pressure (PAWP) ≤15 mm Hg and a pulmonary vascular resistance >3 Wood units. Right heart catheterization remains essential for a diagnosis of PH or PAH. This procedure requires further standardization, including uniformity of the pressure transducer zero level at the midthoracic line, which is at the level of the left atrium. One of the most common problems in the diagnostic workup of patients with PH is the distinction between PAH and PH due to left heart failure with preserved ejection fraction (HFpEF). A normal PAWP does not rule out the presence of HFpEF. Volume or exercise challenge during right heart catheterization may be useful to unmask the presence of left heart disease, but both tools require further evaluation before their use in general practice can be recommended. Early diagnosis of PAH remains difficult, and screening programs in asymptomatic patients are feasible only in high-risk populations, particularly in patients with systemic sclerosis, for whom recent data suggest that a combination of clinical assessment and pulmonary function testing including diffusion capacity for carbon monoxide, biomarkers, and echocardiography has a higher predictive value than echocardiography alone.
Objectives This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH). Background Ambrisentan is an oral, once-daily ...endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH. Methods In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data. Results After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3× the upper limit of normal was ∼2% per year; most of these events were mild and did not lead to discontinuation of drug. Conclusions Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786 )
Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood ...leucocyte telomere lengths had different overall survival.
In this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco).
370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was -0.16 SD 0.23 vs 0.00 0.18; p<0.0001); however, telomere lengths of the Dallas patients with idiopathic pulmonary fibrosis (1.33 SD 0.25) were similar to the 221 patients with other interstitial lung disease diagnoses (1.46 0.24) after adjusting for age, sex, and ethnicity (p=0.47). Telomere length was independently associated with transplant-free survival time for patients with idiopathic pulmonary fibrosis (HR 0.22 95% CI 0.08-0.63; p=0.0048), but not for patients with interstitial lung disease diagnoses other than idiopathic pulmonary fibrosis (HR 0.73 0.16-3.41; p=0.69). The association between telomere length and survival in patients with idiopathic pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing capacity of carbon monoxide, and was replicated in the two independent idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0.11 0.03-0.39, p=0.00066; San Francisco cohort, HR 0.25 0.07-0.87, p=0.029).
Shorter leucocyte telomere lengths are associated with worse survival in idiopathic pulmonary fibrosis. Additional studies will be needed to establish clinically relevant thresholds for telomere length and how this biomarker might affect risk stratification of patients with idiopathic pulmonary fibrosis.
US National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, Harroun Family Foundation, and Nina Ireland Lung Disease Program.
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.
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.
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.
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.
Duration of index hospitalization after lung transplantation (LTx) is an important variable that has not received much attention. We sought to determine independent predictors of prolonged hospital ...length of stay (LOS) and its association with early and late outcomes.
The United Network of Organ Sharing database was queried for adult patients undergoing LTx between 2006 and 2014 (N = 14,320). Patients with dual organ or previous transplantation and patients who died during the first 25 days after LTx were excluded (n = 12,647, mean age 55.2 years ± 13.1). Primary outcome was prolonged LOS (>25 days) (3,251/12,647; 25.7%). Donor, recipient, and procedure-related variables were analyzed as potential predictors of prolonged LOS. Association of prolonged LOS with 1-year and 5-year survival was evaluated using Cox proportional hazards analysis.
Independent predictors of prolonged LOS included serum albumin, lung allocation score, functional status, and need of extracorporeal membrane oxygenation or ventilator support at the time of transplant; donor age >40 years; gender mismatch (female donor to male recipient); donor body mass index; African American ethnicity; ischemic time >6 hours; and double LTx. Prolonged LOS was independently associated with increased mortality at 1 year (hazard ratio, 3.96; 95% confidence interval, 3.48-4.50; p < 0.001) and 5 years (hazard ratio, 2.00; 95% confidence interval, 1.79-2.25; p < 0.001).
A significant proportion of patients have a prolonged LOS after LTx, and several recipient, donor, and procedure-related variables are independent predictors of this outcome. Patients with prolonged LOS after LTx have significantly increased risk of death at 1 year and 5 years.
Objective To determine whether very low birth weight infants (VLBWIs), initially supported with continuous positive airway pressure (CPAP) and then selectively treated with the INSURE (intubation, ...surfactant, and extubation to CPAP; CPAP/INSURE) protocol, need less mechanical ventilation than those supported with supplemental oxygen, surfactant, and mechanical ventilation if required (Oxygen/mechanical ventilation MV). Study design In a multicenter randomized controlled trial, spontaneously breathing VLBWIs weighing 800-1500 g were allocated to receive either therapy. In the CPAP/INSURE group, if respiratory distress syndrome (RDS) did not occur, CPAP was discontinued after 3-6 hours. If RDS developed and the fraction of inspired oxygen (FiO2 ) was >0.35, the INSURE protocol was indicated. Failure criteria included FiO2 >0.60, severe apnea or respiratory acidosis, and receipt of more than 2 doses of surfactant. In the Oxygen/MV group, in the presence of RDS, supplemental oxygen without CPAP was given, and if FiO2 was >0.35, surfactant and mechanical ventilation were provided. Results A total of 256 patients were randomized to either the CPAP/INSURE group (n = 131) or the Oxygen/MV group (n = 125). The need for mechanical ventilation was lower in the CPAP/INSURE group (29.8% vs 50.4%; P = .001), as was the use of surfactant (27.5% vs 46.4%; P = .002). There were no differences in death, pneumothorax, bronchopulmonary dysplasia, and other complications of prematurity between the 2 groups. Conclusion CPAP and early selective INSURE reduced the need for mechanical ventilation and surfactant in VLBWIs without increasing morbidity and death. These results may be particularly relevant for resource-limited regions.
...in previous small clinical series analyzing the effect of therapeutic hypothermia (TH) in patients who undergo PPCI, it was observed that there was an increased rate of stent thrombosis (ST) in ...TH- compared with non-TH-treated patients (2). In the present observational study, even under the prelude of greater hemodynamic support and a higher frequency of hemorrhagic complications in the PPCI-TH-treated patients, the incidence of ST was almost identical to that of patients not treated with TH. ...under the need of further prospective trials, we believe that adequate antithrombotic management could be achieved in this population with both the progressive introduction of third-generation P2Y12 inhibitors and consideration that the route (intravenous aspirin and crushed nasogastric P2Y12) (5) and time (before PPCI) of administration may influence the final result.
Abstract Objective Pulmonary 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. Methods PAH 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. Results Thirty-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. Conclusion The 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.
Background Cerebral venous thrombosis (CVT) is a rare form of cerebrovascular disease that is usually not mentioned in multicenter registries on all-type acute stroke. We aimed to describe the ...experience on hospitalized patients with CVT in a Mexican multicenter registry on acute cerebrovascular disease. Methods CVT patients were selected from the RENAMEVASC registry, which was conducted between 2002 and 2004 in 25 Mexican hospitals. Risk factors, neuroimaging, and 30-day outcome as assessed by the modified Rankin scale (mRS) were analyzed. Results Among 2000 all-type acute stroke patients, 59 (3%; 95% CI, 2.3-3.8%) had CVT (50 women; female:male ratio, 5:1; median age, 31 years). Puerperium (42%), contraceptive use (18%), and pregnancy (12%) were the main risk factors in women. In 67% of men, CVT was registered as idiopathic, but thrombophilia assessment was suboptimal. Longitudinal superior sinus was the most frequent thrombosis location (78%). Extensive (>5 cm) venous infarction occurred in 36% of patients. Only 81% of patients received anticoagulation since the acute phase, and 3% needed decompressive craniectomy. Mechanical ventilation (13.6%), pneumonia (10.2%) and systemic thromboembolism (8.5%) were the main in-hospital complications. The 30-day case fatality rate was 3% (2 patients; 95% CI, 0.23-12.2%). In a Cox proportional hazards model, only age <40 years was associated with a mRS score of 0 to 2 (functional independence; rate ratio, 3.46; 95% CI, 1.34-8.92). Conclusions The relative frequency of CVT and the associated in-hospital complications were higher than in other registries. Thrombophilia assessment and acute treatment was suboptimal. Young age is the main determinant of a good short-term outcome.
Pulmonary arterial hypertension (PAH) is a progressive disease with lung transplantation as the only option for those patients refractory to medical therapy. Although several equations have been ...developed to predict PAH patient survival, it is unclear whether they can predict survival for patients awaiting transplantation.
Data were analyzed on 827 patients listed since 1991 on the Scientific Registry of Transplant Recipients. Overall survival and survival for patients listed prior to and after January 1, 2006 was estimated using the Kaplan-Meier (K-M) method and compared with predicted survival from the pulmonary hypertension connection (PHC) and lung allocation system (LAS) equations. A new equation using a novel model selection algorithm for correlated covariates and missing data was developed using clinical factors and variables in the LAS score. Model validation statistics were calculated and averaged across 500 bootstrap resamples within each of 5 imputation data sets. K-M with 95% confidence intervals and receiver-operator characteristic (ROC) curves assessed model performance.
PHC predicted overall survival but underestimated and overestimated survival for those listed pre- and post-2006, respectively. The best model included baseline 6-minute walk distance (6MWD), invasive cardiac output and resting oxygen requirement (O2). Factors associated with 1-year waitlist survival included: resting O2 amount; invasive hemodynamics; 6MWD; and functional class. The new equation by ROC analysis outperformed the LAS and PHC equations.
Current prediction models overestimate survival for PAH patients listed for transplant in the LAS era. This new survival equation can help guide clinicians caring for PAH patients with progression of disease requiring transplant.
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