Nika Skoro-Sajer

Predictors of Outcome in Chronic Thromboembolic Pulmonary Hypertension

Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intraluminal thrombus organization and fibrous obliteration of pulmonary arteries. Recently, associated medical conditions such as splenectomy, ventriculoatrial shunt for the treatment of hydrocephalus, permanent central intravenous lines, inflammatory bowel disease, and osteomyelitis were found to be associated with the development of CTEPH. The study aim was to define the impact of these novel risk factors on survival. Methods and Results— Between January 1992 and December 2006, 181 patients diagnosed with CTEPH were tracked with the use of our centers customized computer database. A Cox regression model was used to examine relations between survival and associated medical conditions, age, sex, hemodynamic parameters, modified New York Heart Association functional class at diagnosis, CTEPH type, pulmonary endarterectomy, and anti-cardiolipin antibodies/lupus anticoagulant. During a median observation time of 22.1 (range, 0.03 to 152) months, the clinical end point of cardiovascular death or lung transplantation occurred in 48 cases (27%). Pulmonary endarterectomy (hazard ratio, 0.14; 95% CI, 0.05 to 0.41; P=0.0003), associated medical conditions (hazard ratio, 3.17; 95% CI, 1.70 to 5.92; P=0.0003), and pulmonary vascular resistance (hazard ratio, 1.02; 95% CI, 1.00 to 1.04; P=0.04) were predictors of survival. Thirty-day postoperative mortality (24% versus 9%) and the incidence of postoperative pulmonary hypertension (92% versus 20%) were substantially higher in patients with associated medical conditions. Conclusions— CTEPH-predisposing medical conditions, such as splenectomy, permanent central intravenous lines, and certain inflammatory disorders, predict poor survival in CTEPH.

Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) results from non‐resolving pulmonary thromboemboli that are resistant to plasmatic anticoagulation. Because of a secondary pulmonary arteriopathy accompanying major vessel obstruction, the disorder may be a target for vasodilator therapy. Objectives: In an open‐label uncontrolled study, we investigated the prostacyclin analog treprostinil given s.c. in patients with severe inoperable CTEPH. Methods: Between September 1999 and September 2005, 25 patients were included if their World Health Organization (WHO) functional class was III or IV, if their six‐minute walking distance (6‐MWD) ≤ 380 m, and if they had undergone at least one hospitalization for right heart decompensation within the prior six months, albeit not within one month before treatment start. Right heart catheterization was performed at baseline and after a minimum of 12 months (range: 12–33 months) of treatment. Treprostinil plasma concentrations were determined after at least six months of treatment. A historical group of 31 patients at our center with inoperable CTEPH matched for disease severity was used for comparative analyses. Results: Treprostinil‐treated patients demonstrated significant improvements in 6‐MWD (P = 0.01), WHO functional class (P = 0.001), B‐type brain natriuretic peptide plasma levels (P = 0.02), cardiac outputs (P = 0.007) and pulmonary vascular resistances (P = 0.01) after 19 ± 6.3 months. Treprostinil plasma concentrations correlated with drug dose (P < 0.001), indicating stable absorption over time. Long‐term survival was significantly better than in controls. Conclusions: Treprostinil improves exercise capacity, hemodynamics and survival in patients with severe inoperable CTEPH. We speculate that the effects may be explained by a combined vasodilatatory, platelet‐antagonistic and potential antiproliferative action of the drug.

Pulmonary Vascular Reactivity and Prognosis in Patients With Chronic Thromboembolic Pulmonary Hypertension A Pilot Study

Background— Surgical pulmonary endarterectomy is the preferred treatment for chronic thromboembolic pulmonary hypertension. Persistent pulmonary hypertension after pulmonary endarterectomy has been recognized as a major determinant of poor outcome. We tested whether acute vasoreactivity identifies chronic thromboembolic pulmonary hypertension patients prone to develop persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and whether the degree of acute vasoreactivity affects survival or freedom from lung transplantation. Methods and Results— Right-sided heart catheterization at baseline and after inhalation of 40 ppm nitric oxide for 20 minutes was performed in 103 patients (56.3±15.3 years old, 53 women). Reductions in mean pulmonary arterial pressure (&Dgr;mPAP; −8.8±12.6%; P<0.0001) and pulmonary vascular resistance (−16.1±18.1%; P<0.0001) and an increase in mixed venous saturation during inhaled nitric oxide (9.1±11.6%; P<0.0001) were observed. Sixty-two patients underwent pulmonary endarterectomy after a median of 49 days (25th and 75th percentiles: 24 and 123 days). Operated patients were followed up for a median of 70.9 months (25th and 75th percentiles: 14 and 97 months). Change in mPAP during inhaled NO was identified as a predictor of persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. Patients experiencing a reduction in mPAP >10.4% with nitric oxide inhalation had a better postoperative outcome. A significant correlation was found between &Dgr;mPAP and immediate postoperative pulmonary vascular resistance (r=0.5, P<0.0001). Conclusions— A total of 80 (77.7%) of 103 patients demonstrated acute pulmonary vascular reactivity of some degree. A decrease in mPAP >10.4% under inhaled nitric oxide is a predictor of long-term survival and freedom from lung transplantation in adult patients with chronic thromboembolic pulmonary hypertension who are undergoing pulmonary endarterectomy.

Heart-type fatty acid-binding protein for risk assessment of chronic thromboembolic pulmonary hypertension

Heart-type fatty acid-binding protein (H-FABP) is a reliable marker of myocardial injury and was recently identified as a predictor of outcome in acute pulmonary embolism. The aim of the present study was to investigate the prognostic value of H-FABP in chronic thromboembolic pulmonary hypertension (CTEPH). In total, 93 consecutive patients with CTEPH were studied. During long-term follow-up (median duration 1,260 days, interquartile range (IQR) 708–2,460 days), 46 (49%) patients had an adverse outcome, defined as CTEPH-related death, lung transplantation or persistent pulmonary hypertension after pulmonary endarterectomy (PEA). Baseline H-FABP levels in plasma ranged from 0.69–24.3 ng·mL−1 (median (IQR) 3.41 (2.28–4.86) ng·mL−1). Cox regression analysis revealed a hazard ratio of 1.10 (95% confidence interval 1.04–1.18) for each increase of H-FABP by 1 ng·mL−1, and continuous elevations of H-FABP emerged as an independent predictor of adverse outcome by multivariable analysis. PEA was performed in 52 patients and favourably affected the long-term outcome. Kaplan–Meier analysis revealed that patients with baseline H-FABP concentrations >2.7 ng·mL−1, the median value of the biomarker in the surgically treated population, had a lower probability of event-free survival after PEA. Heart-type fatty acid-binding protein is a promising novel biomarker for risk stratification of patients with chronic thromboembolic pulmonary hypertension.

A noninvasive algorithm to exclude pre-capillary pulmonary hypertension

Current guidelines recommend right heart catheterisation (RHC) in symptomatic patients at risk of pre-capillary pulmonary hypertension (PH) with echocardiographic systolic pulmonary artery pressures ≥36 mmHg. Growing awareness for PH, a high prevalence of post-capillary PH and the inability to distinguish between pre- and post-capillary PH by echocardiography have led to unnecessary RHCs. The aim of our study was to assess whether standard noninvasive diagnostic procedures are able to safely exclude pre-capillary PH. Data from 251 patients referred for suspicion of pre-capillary PH were used to develop a noninvasive diagnostic decision tree. A prospectively collected data set of 121 consecutive patients was utilised for temporal validation. According to the decision tree, patients were stratified by the presence or absence of an electrocardiographic right ventricular strain pattern (RVS) and serum N-terminal brain natriuretic peptide (NT-proBNP) levels below and above 80 pg·mL−1. In the absence of RVS and elevated NT-proBNP, none of the patients in the prospective validation cohort were diagnosed with pre-capillary PH by RHC. Combining echocardiography with the diagnostic algorithm increased specificity to 19.3% (p = 0.0009), while sensitivity remained at 100%. Employing ECG and NT-proBNP on top of echocardiography helps recognise one false positive case per five patients referred with dyspnoea and echocardiographic suspicion of PH, while not missing true pre-capillary PH.

Surgical specimens, haemodynamics and long-term outcomes after pulmonary endarterectomy

Background Chronic thromboembolic pulmonary hypertension is surgically curable by pulmonary endarterectomy (PEA). It is unclear whether PEA impacts primarily steady state right ventricular afterload (ie, pulmonary vascular resistance (PVR)) or pulsatile right ventricular afterload (ie, pulmonary arterial compliance (CPA)). Our objectives were to (1) quantify PEA specimens and measure the impact of PEA on PVR and CPA in a structure/function study and (2) analyse the effects of haemodynamic changes on long-term survival/freedom of lung transplantation in an outcome study. Methods Thrombi were laid out, weighed, photographed and measured. PVR, CPA and resistance times compliance (RC-time) were assessed at baseline, within 4 days after PEA (‘immediately postoperative’) and 1 year after PEA, in 110 consecutive patients who were followed for 34.5 (11.9; 78.3) months. Results Lengths and numbers of PEA specimen tails were inversely correlated with immediate postoperative PVR (p<0.0001, r=−0.566; p<0.0001, r=−0.580). PVR and CPA normalised immediately postoperatively while RC-time remained unchanged. Immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation (p<0.0001). Patients with immediate postoperative PVR<590 dynes.s.cm−5 had better long-term outcomes than patients with PVR≥590 dynes.s.cm−5 (p<0.0001, respectively). Conclusions PEA immediately decreased PVR and increased CPA under a constant RC-time. However, immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation. Our study confirms the importance of a complete, bilateral surgical endarterectomy. Low PVR measured immediately postoperative predicts excellent long-term outcome.

Treprostinil for pulmonary hypertension

Treprostinil is a stable, long-acting prostacyclin analogue which can be administered as a continuous subcutaneous infusion using a portable miniature delivery system. Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor prognosis. Side effects include facial flush, headache, jaw pain, abdominal cramping, and diarrhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and infusion site pain which may make further treatment impossible in 7%–10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting efficacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2–3 times those given subcutaneously, appear to be needed to obtain the same efficacy. Preliminary results of a randomized controlled trial of inhaled treprostinil on top of bosentan and sildenafil therapies have shown significance on the primary endpoint, which was exercise capacity as assessed by the distance walked in 6 minutes. Trials of oral formulations of treprostinil have been initiated.

Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension

BACKGROUND Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patient sub-sets, and study durations. In addition, common practice is to start oral therapies ahead of the more potent and titratable prostanoid therapies, despite advanced disease states at diagnosis. The objectives of our prospective registry were to evaluate long-term effects on functional class, 6-minute walking distance, hemodynamics, and survival, and also long-term tolerability of first-line sub-cutaneous treprostinil, a prostacyclin analog, in patients with severe pulmonary hypertension. METHODS Data were collected from patients with functional class III/IV pre-capillary pulmonary hypertension (Dana Point groups 1 and 4; mean right arterial pressure ≥ 10 mmHg, and/or cardiac index ≤ 2.2 liters/min/m(2)). Treprostinil dose adjustments were driven by clinical symptoms and side effects. RESULTS The study included 111 patients (1999 to 2010). Of these, 13 (12%) stopped treatment prematurely because of drug side effects, 11 (9.9%) underwent double lung transplantation, and 49 (44.1%) died of any cause (41 on treatment, 8 after early drug discontinuation). Overall survival rates at 1, 5, and 9 years were 84%, 53%, and 33%. In patients who were able to tolerate treatment > 6 months, survival rates were 57% at 9 years. CONCLUSION First-line treatment of severe pre-capillary pulmonary hypertension with sub-cutaneous treprostinil is safe and efficacious over many years. If up-titration beyond 6 months is tolerated, effective doses are reached and outcomes are good.

A Clinical Comparison of Slow- and Rapid-Escalation Treprostinil Dosing Regimens in Patients with Pulmonary Hypertension

AbstractBackground and objective: Subcutaneous treprostinil is an effective treatment for pulmonary arterial hypertension (PAH). A previous pivotal study indicated that infusion site pain was dose dependent and resulted in suboptimal dose escalation by week 12 and a reduced clinical benefit. We hypothesized that a rapid-escalation treprostinil dosing regimen would be as safe and effective as a slow-escalation dosing regimen. Methods: Twenty-three patients received treprostinil to treat PH of various aetiologies and were randomized into two groups. Group 1 (11 patients: seven females and four males, aged 51.7 ± 15.4 years) received a slowescalation regimen, and group 2 (12 patients: ten females and two males, aged 51.3 ± 16.7 years) were exposed to rapid dose escalation. The dose escalation, exercise capacity (a 6-minute walk test [6WT] or a shuttle walk test [SWT]), WHO classification, blood pressure, heart rate, respiration rate, baseline haemodynamics and adverse events were followed up for 12 weeks. Results: Baseline haemodynamics did not differ significantly between the treatment groups. At follow-up, the treprostinil dose reached 12.9 ± 2.7 ng/kg/min in group 1 and 20.3 ± 5.8 ng/kg/min in group 2 (p < 0.01). The patients’ WHO classification improved significantly (p < 0.05), with no difference between the groups. Improvement of exercise capacity was greater in group 2 (6WT and SWT, p < 0.05). Infusion site pain occurred in 81.8% of group 1 and in 58.3% of group 2 (p < 0.05) patients. Other adverse events and changes in the heart rate, respiration rate and blood pressure were similar in both groups. Conclusion: The rapid-dosing regimen is as safe and effective as the slow-escalation regimen and may be associated with even better clinical outcomes. Infusion site pain is not dose dependent.

Bosentan therapy for pulmonary arterial hypertension associated with hereditary haemorrhagic telangiectasia

Hereditary haemorrhagic telangiectasia (HHT) is a disorder of arteriovenous malformations and telangiectases. In rare cases affected individuals may develop typical pulmonary arterial hypertension (PAH). Vasodilator therapy has not been recommended because of a potential increase in arteriovenous shunt volume.