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ABSTRACT: We assessed the safety, tolerability and preliminary efficacy of riociguat, a soluble guanylate cyclase stimulator, in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD).In this open-label, uncontrolled pilot trial, patients received oral riociguat (1.0-2.5 mg t.i.d.) for 12 weeks (n=22), followed by an ongoing long-term extension (interim analysis at 12 months) in those eligible (n=15). Primary endpoints were safety and tolerability. Secondary endpoints included haemodynamic changes and 6-minute walk distance (6MWD).Overall, 104 adverse events were reported, of which 25 were serious; eight of the latter were considered drug-related. After 12 weeks of therapy, mean cardiac output increased (4.4±1.5 L·min(-1) to 5.5±1.8 L·min(-1)), pulmonary vascular resistance (PVR) decreased (648±207 dyn.s.cm(-5) to 528±181 dyn.s.cm(-5)) and mean pulmonary artery pressure (PAPm) remained unchanged compared with baseline. Arterial oxygen saturation decreased but mixed-venous oxygen saturation slightly increased. The 6MWD increased from 325±96 m at baseline to 351±111 m after 12 weeks.Riociguat was well tolerated by most patients and improved cardiac output and PVR, but not PAPm. Further studies are necessary to evaluate the safety and efficacy of riociguat in patients with PH-ILD.
European Respiratory Journal 08/2012; · 5.89 Impact Factor
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Horst Olschewski,
M. M. Hoeper,
M. M. Borst,
R. Ewert,
E. Grünig,
F.-X. Kleber,
B. Kopp,
C. Opitz,
F. Reichenberger,
A. Schmeisser,
D. Schranz,
I. Schulze-Neick, H. Wilkens,
J. Winkler,
H. Worth
Clinical Research in Cardiology 04/2012; 96(5):301-330. · 2.95 Impact Factor
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Ekkehard Grünig,
Mona Lichtblau,
Nicola Ehlken,
Hossein A Ghofrani,
Frank Reichenberger,
Gerd Staehler,
Michael Halank,
Christine Fischer,
Hans-Jürgen Seyfarth,
Hans Klose,
Andreas Meyer,
Stephan Sorichter, Heinrike Wilkens,
Stephan Rosenkranz,
Christian Opitz,
Hanno Leuchte,
Gabriele Karger,
Rudolf Speich,
Christian Nagel
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ABSTRACT: The objective of this prospective study was to assess safety and efficacy of exercise training in a large cohort of patients with different forms and World Health Organization (WHO) functional classes of chronic pulmonary hypertension (PH). 183 patients with PH (pulmonary arterial hypertension (PAH), chronic thromboembolic PH and PH due to respiratory or left heart diseases received exercise training in hospital for 3 weeks and continued at home. Adverse events have been monitored during the in-hospital training programme. Efficacy parameters were evaluated at baseline, and after 3 and 15 weeks. After 3 and 15 weeks, patients significantly improved the distance walked in 6 min (6MWD) compared to baseline, scores of quality of life, WHO functional class, peak oxygen consumption, oxygen pulse, heart rate and systolic pulmonary artery pressure at rest and maximal workload. The improvement in 6MWD was similar in patients with different PH forms and functional classes. Even in severely affected patients (WHO functional class IV), exercise training was highly effective. Adverse events, such as respiratory infections, syncope or presyncope, occurred in 13% of patients. Exercise training in PH is an effective but not a completely harmless add-on therapy, even in severely diseased patients, and should be closely monitored.
European Respiratory Journal 02/2012; 40(1):84-92. · 5.89 Impact Factor
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S Rosenkranz,
J Behr,
R Ewert,
H A Ghofrani,
E Grünig,
M Halank,
M M Hoeper,
H H Leuchte,
H Olschewski,
A Schmeisser,
R Speich, H Wilkens,
C F Opitz
DMW - Deutsche Medizinische Wochenschrift 12/2011; 136(50):2601-16; quiz 2617-20. · 0.53 Impact Factor
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H Wilkens,
I Lang,
J Behr,
T Berghaus,
C Grohe,
S Guth,
M M Hoeper,
T Kramm,
U Krüger,
F Langer,
H-J Schäfers,
M Schmidt,
H-J Seyfarth,
T Wahlers,
H Worth,
E Mayer
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ABSTRACT: In the 2009 European Guidelines on pulmonary hypertension one section covers aspects of pathophysiology, diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The practical implementation of the guidelines for this disease is of crucial importance, because CTEPH is a form of pulmonary hypertension which can be surgically cured. It is, however, frequently diagnosed late in the course of disease and often treated not correctly. In the European Guidelines CTEPH is addressed relatively briefly, although it is a common form of PH which is often overlooked. Any patient with unexplained PH should be evaluated for the presence of CTEPH. A ventilation/perfusion lung scan is recommended as the first step to exclude CTEPH. If the ventilation/perfusion lung scan or multislice CT angiography reveals perfusions defects suggesting the diagnosis of CTEPH, the patient should be referred to a centre with expertise in the medical and surgical management of these patients. After diagnosis of CTEPH the case has to be reviewed by an experienced surgeon in a PEA centre for assessment of operability. The recommendations of the European guidelines are summarized in the current manuscript with additional comments regarding diagnosis and treatment according to most recent evidence.
DMW - Deutsche Medizinische Wochenschrift 10/2010; 135 Suppl 3:S125-30. · 0.53 Impact Factor
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ABSTRACT: This study aimed to describe health care provision, resource consumption and related costs, as well as treatment patterns and quality of life in adult patients with pulmonary arterial hypertension (PAH) in Germany. Data for this retrospective and prospective cost-of-illness-study were derived from hospitals, general practitioners and patients. Costs were evaluated from the perspective of third party payer and patient. Quality of life data were collected by using three validated instruments. A total of 167 patients were enrolled at 10 hospitals. Time period from first occurrence of symptoms to confirmed diagnosis of PAH was 2.3 years on average. Mean number of GP visits was 1.5 per patient per month, and within 15 months, inpatient stays were reported for 50% of patients. The ratio of combination therapy to single-drug therapy for endothelin receptor antagonists, phosphodiesterase-5-inhibitor and prostacyclin analogues increased significantly during 15 months. Treatment costs were, on average, euro47,400 per patient per year, arising mainly from drugs. Compared to the general population, quality of life of PAH patients was considerably impaired. This is the first study which evaluated aspects of the medical and economic consequences of PAH based on a large cohort of PAH patients in Germany.
Respiratory medicine 02/2010; 104(6):902-10. · 2.33 Impact Factor
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Horst Olschewski,
M M Hoeper,
M M Borst,
R Ewert,
E Grünig,
F-X Kleber,
B Kopp,
C Opitz,
F Reichenberger,
A Schmeisser,
D Schranz,
I Schulze-Neick, H Wilkens,
J Winkler,
H Worth
Clinical Research in Cardiology 06/2007; 96(5):301-30. · 2.95 Impact Factor
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H Olschewski,
M M Hoeper,
M M Borst,
R Ewert,
E Grünig,
F-X Kleber,
B Kopp,
C Opitz,
F Reichenberger,
A Schmeisser,
D Schranz,
I Schulze-Neick, H Wilkens,
J Winkler,
H Worth
Pneumologie 01/2007; 60(12):749-71.
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M M Hoeper,
H Leuchte,
M Halank, H Wilkens,
F J Meyer,
H J Seyfarth,
R Wensel,
F Ripken,
H Bremer,
S Kluge,
G Hoeffken,
J Behr
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ABSTRACT: Addition of inhaled iloprost to bosentan may have beneficial effects in patients with idiopathic pulmonary arterial hypertension (IPAH). A multicentre, open, randomised, controlled trial was performed to assess the safety and efficacy of inhaled iloprost in patients with IPAH who had already been treated with bosentan. The trial was terminated early after a futility analysis predicted failure with respect to the predetermined sample size. At that time, 40 patients were randomised to receive either bosentan alone (control group) or bosentan plus inhaled iloprost (combination group) for a 12-week period. The primary end-point, change in 6-min walking distance, was not met (mean changes +1 m and -9 m in the control and combination group, respectively). These results may have been skewed by three outliers in the iloprost group who presented with severe clinical worsening. None of the secondary end-points including functional class, peak oxygen uptake, and time to clinical worsening differed significantly between groups. The current study failed to show a positive effect of adding inhaled iloprost to bosentan in idiopathic pulmonary arterial hypertension patients. Further studies involving larger sample sizes and long-term follow-up are needed to determine the efficacy of adding inhaled iloprost to bosentan in patients with idiopathic pulmonary arterial hypertension.
European Respiratory Journal 11/2006; 28(4):691-4. · 5.89 Impact Factor
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ABSTRACT: For patients with pulmonary arterial hypertension (PAH) two first line therapies - iloprost inhalation (Ventavis) and bosentan (Tracleer) -- are available in Germany. A third substance, sildenafil, is already approved in the US and will be approved for this indication in the European Union soon. Patients with PAH can be stabilized or improved with a specific mono-therapy for a limited period of time only. Therefore, the question arises when and how to initiate treatment escalation. The available data from controlled clinical trials are insufficient to give a definite answer to these questions. Moreover, it is still unclear which combination of the above mentioned substances may be superior in the treatment of PAH. On the other hand, combination therapy is already reality in clinical practice. Based on this background experts from specialized centers dealing with PAH discussed the scientific basis of the role of combination therapy in PAH patients during a workshop held on April 22/23. 2005 in Wiesbaden. The goal of this workshop was to formulate a common position with regard to combination therapy of PAH on the basis of the available scientific data and clinical experience.
Pneumologie 11/2005; 59(10):730-5.
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R Koehler,
E Grünig,
M W Pauciulo,
M M Hoeper,
H Olschewski, H Wilkens,
M Halank,
J Winkler,
R Ewert,
H Bremer,
S Kreuscher,
B Janssen,
W C Nichols
Journal of Medical Genetics 01/2005; 41(12):e127. · 6.36 Impact Factor
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ABSTRACT: As there is controversy about changes in lung function in primary pulmonary hypertension (PPH), lung mechanics were assessed with a focus on expiratory airflow in relation to pulmonary haemodynamics.
A cross sectional study was performed in 64 controls and 171 patients with PPH (117 women) of mean (SD) age 45 (13) years, pulmonary artery pressure (PAPmean) 57 (15) mm Hg, and pulmonary vascular resistance 1371 (644) dyne.s/cm(5).
Mean (SD) total lung capacity was similar in patients with PPH and controls (98 (12)% predicted v 102 (17)% predicted, mean difference -4 (95% confidence interval (CI) -7.89 to -0.11); residual volume (RV) was increased (118 (24)% predicted v 109 (27)% predicted, mean difference 9 (95% CI 1.86 to 16.14); and vital capacity (VC) was decreased (91 (16)% predicted v 102 (10)% predicted, mean difference -11 (95% CI 15.19 to -6.80). RV/TLC was increased (117 (27)% predicted v 97 (29)% predicted, mean difference 20 (95% CI 12.3 to 27.8)) and correlated with PAPmean (r=0.31, p<0.001). In patients with PAPmean above the median of 56 mm Hg, RV/TLC was further increased (125 (32)% predicted v 111 (22)% predicted, mean difference -14 (95% CI -22.2 to -5.8)). Expiratory flow-volume curves were reduced and curvilinear in patients with PPH.
Peripheral airway obstruction is common in PPH and is more pronounced in severe disease. This may contribute to symptoms. Reversibility of bronchodilation and relation to exercise capacity need further evaluation.
Thorax 07/2002; 57(6):473-6. · 6.84 Impact Factor
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J Niedermeyer,
B Bewig,
T Bickhardt,
R Ewert,
P Fischer,
M Hamm,
J Lill,
F J Meyer,
I Otterbach,
C Vogelmeier,
F Wagner, H Wilkens,
H Worth
Pneumologie 09/2001; 55(8):396-400.
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ABSTRACT: Pulmonary thromboendarterectomy (PTE) for chronic thromboembolic pulmonary hypertension is a challenging procedure with a considerable mortality. The aim of this investigation was to identify risk factors influencing mortality and operative results.
Between October 1995 and August 2000, 69 patients (age 54 years; 34 women; mean New York Heart Association (NYHA) stage 3.4) underwent PTE. The preoperative pulmonary vascular resistance (PVR) was 988+/-554 dynes x s x cm(-5), mean pulmonary artery pressure 50+/-12 mmHg, right atrial pressure (RAP) 11.5+/-4 mmHg. Hospital mortality was 10.1% (n=7/69). Mean postoperative PVR on the 2nd day was 324+/-188 dynes x s x cm(-5). Pulmonary angiography was reviewed for number of involved segments (mean 9.3+/-2) and bronchial arteries diameter (BAD; mean 4.6+/-1.6 mm). A univariate and multivariate analysis was performed to determine preoperative risk factors for hospital death and inadequate hemodynamic improvement.
By univariate analysis, mortality was influenced by age (P=0.04), right atrial pressure (P=0.009), NYHA (P=0.02) and the number of angiographically involved segments (P=0.02). Sex, left ventricular function, presence of coronary artery disease and bronchial artery diameter did not show correlation with mortality. Inadequate hemodynamic improvement in a dichotomized analysis (PVR > or =500 dynes x s x cm(-5), n=11, and PVR < 500 dynes x s x cm(-5), n=58), assessed by univariate analysis, was significantly influenced by age (P=0.02), preoperative PVR (P=0.01), NYHA (P=0.002), RAP (P=0.02) and female sex (P=0.02). Multivariate analysis identified age (P=0.1), RAP (P=0.002) and female sex (P=0.007) as risk factors for inferior hemodynamic improvement.
Preoperative parameters can be utilized to assess postoperative mortality and hemodynamic improvement after pulmonary thromboendarterectomy. Patient age and clinical deterioration of pulmonary hypertension are considerable preoperative factors influencing hospital mortality. Inadequate postoperative hemodynamic improvement is affected by severity of disease and female sex.
European Journal of Cardio-Thoracic Surgery 06/2001; 19(6):771-6. · 2.55 Impact Factor
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ABSTRACT: Inhaled aerosolized iloprost, a stable prostacyclin analogue, has been considered a selective pulmonary vasodilator in the management of pulmonary hypertension.
To assess the efficacy of inhaled iloprost in the treatment of life-threatening pulmonary hypertension.
Open, uncontrolled, multicenter study.
Intensive care units and pulmonary hypertension clinics at six university hospitals in Germany.
19 patients who had progressive right-heart failure despite receiving maximum conventional therapy (12 with primary pulmonary hypertension, 3 with pulmonary hypertension related to collagen vascular disease without lung fibrosis, and 4 with secondary pulmonary hypertension).
Inhaled iloprost, 6 to 12 times daily (50 to 200 microg/d).
Right-heart catheterization and distance walked in 6 minutes at baseline and after 3 months of therapy.
During the first 3 months of therapy, New York Heart Association functional class improved in 8 patients and was unchanged in 7 patients. Four patients died, 3 of right-heart failure and 1 of sepsis. The acute hemodynamic response to inhaled iloprost was predominant pulmonary vasodilatation with little systemic effect at baseline and at 3 months (data available for 12 patients). Hemodynamic variables were improved at 3 months, and the distance walked in 6 minutes improved by 148 m (95% CI, 4.5 to 282 m; P = 0.048). Of the 15 patients who continued to use inhaled iloprost, 8 stopped: Four had lung transplantation, 1 switched to intravenous prostacyclin therapy, and 3 died. Seven patients are still receiving inhaled iloprost (mean +/-SD) duration of therapy, 536 +/- 309 days; mean dosage, 164 +/- 38 microg/d).
Inhaled iloprost may offer a new therapeutic option for improvement of hemodynamics and physical function in patients with life-threatening pulmonary hypertension and progressive right-heart failure that is refractory to conventional therapy.
Annals of internal medicine 04/2000; 132(6):435-43. · 16.73 Impact Factor
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ABSTRACT: We sought to compare the acute hemodynamic effects of inhaled nitric oxide (NO) and aerosolized iloprost in primary pulmonary hypertension (PPH).
Inhalation of the stable prostacyclin analogue iloprost has recently been described as a novel therapeutic strategy for PPH and may offer an alternative to continuous intravenous infusion of prostacyclin or inhalation of NO.
During right heart catheterization, 35 patients with PPH sequentially inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the effects on hemodynamics and blood gases were monitored.
Both NO and iloprost caused significant increases in cardiac output, mixed-venous oxygen saturation and stroke volume as well as significant decreases in pulmonary artery pressure and pulmonary vascular resistance, whereas only inhaled iloprost significantly increased the arterial PO2 (p = 0.01). Compared with inhaled NO, aerosolized iloprost was more effective in reducing pulmonary artery pressure (-8.3 +/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary vascular resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x cm(-5); p < 0.0001). Furthermore, aerosolized iloprost caused a significantly greater increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min vs. +0.3 +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the mixed-venous oxygen saturation (p = 0.003).
During acute drug testing, aerosolized iloprost was more potent than inhaled NO as a pulmonary vasodilator in PPH at the doses used in this study.
Journal of the American College of Cardiology 02/2000; 35(1):176-82. · 14.16 Impact Factor
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H Olschewski,
M M Hoeper,
J Behr,
R Ewert,
A Meyer,
M M Borst,
J Winkler,
M Pfeifer, H Wilkens,
H A Ghofrani,
S. Nikkho,
W Seeger
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ABSTRACT: AIMS: To investigate the long-term safety of inhaled iloprost in patients with pulmonary hypertension (pH), including idiopathic PAH (IPAH group) and other forms of pulmonary hypertension (PHother). METHODS AND RESULTS: Sixty-three patients (IPAH group, n=40, PHother n=23) were enrolled to receive inhaled iloprost either from baseline or after 3 months in a prospective, open-label 2-year study. Iloprost was inhaled 6-9 times daily with a night pause employing a jet nebulizer delivering an inhaled single dose of 4microg at the mouthpiece. In the case of side effects the single dose was reduced to 2microg. Sixty patients received at least 1 dose of inhaled iloprost. Thirty-six patients completed at least 630 days of therapy (25 IPAH, 11 PHother), 19 patients dropped out prematurely and 8 patients died (3 IPAH, 5 PHother). There were no drug-induced toxicities and only mild to moderate side effects. The most common side effects were coughing and flushing. Two-year survival was estimated at 85% (IPAH group 91%, PHother 78%). A modified analysis was performed to correct for differential drop-out. It included follow-up data from the premature discontinuations and revealed a 2-year survival of 87% [95% CI, 76%-98%] in the IPAH group while the predicted survival was 63%. The iloprost dose increased by 16% over 2 years. CONCLUSION: Inhaled iloprost is well tolerated as long-term therapy and no substantial dose increase is required. Although uncontrolled, the data suggest a long-term clinical benefit from continued therapy with inhaled iloprost.
Respir Med, v.104, 731-40.
