Rudolf Speich

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Results From an International Prospective Registry

Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results— The international registry included 679 newly diagnosed (≤6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%– 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions— Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension–targeted treatments. # Clinical Perspective {#article-title-40}Background— Chronic thromboembolic pulmonary hypertension (CTEPH) is often a sequel of venous thromboembolism with fatal natural history; however, many cases can be cured by pulmonary endarterectomy. The clinical characteristics and current management of patients enrolled in an international CTEPH registry was investigated. Methods and Results— The international registry included 679 newly diagnosed (⩽6 months) consecutive patients with CTEPH, from February 2007 until January 2009. Diagnosis was confirmed by right heart catheterization, ventilation-perfusion lung scintigraphy, computerized tomography, and/or pulmonary angiography. At diagnosis, a median of 14.1 months had passed since first symptoms; 427 patients (62.9%) were considered operable, 247 (36.4%) nonoperable, and 5 (0.7%) had no operability data; 386 patients (56.8%, ranging from 12.0%– 60.9% across countries) underwent surgery. Operable patients did not differ from nonoperable patients relative to symptoms, New York Heart Association class, and hemodynamics. A history of acute pulmonary embolism was reported for 74.8% of patients (77.5% operable, 70.0% nonoperable). Associated conditions included thrombophilic disorder in 31.9% (37.1% operable, 23.5% nonoperable) and splenectomy in 3.4% of patients (1.9% operable, 5.7% nonoperable). At the time of CTEPH diagnosis, 37.7% of patients initiated at least 1 pulmonary arterial hypertension–targeted therapy (28.3% operable, 53.8% nonoperable). Pulmonary endarterectomy was performed with a 4.7% documented mortality rate. Conclusions— Despite similarities in clinical presentation, operable and nonoperable CTEPH patients may have distinct associated medical conditions. Operability rates vary considerably across countries, and a substantial number of patients (operable and nonoperable) receive off-label pulmonary arterial hypertension–targeted treatments.

Lung Transplantation for Lymphangioleiomyomatosis

BACKGROUND Lymphangioleiomyomatosis is a rare disease of unknown origin that usually leads to progressive deterioration of lung function and eventual death from respiratory failure. It occurs in women of reproductive age and people with tuberous sclerosis. Lung transplantation is a recent therapeutic approach. METHODS We conducted a retrospective study by questionnaire of 34 patients, treated at 16 transplantation centers, who underwent lung transplantation for end-stage lymphangioleiomyomatosis between 1983 and 1995. RESULTS Of the 34 patients, 27 received single-lung transplants; 6, bilateral transplants; and 1, a heart-lung transplant. As of August 31, 1995, the actuarial survival calculated by the Kaplan-Meier method was 69 percent after one year and 58 percent after two years. Eighteen patients were alive 33 +/- 20 months (range, 3 to 74) after transplantation. Forced expiratory volume in one second increased from 24 +/- 12 percent of the predicted value before transplantation to 48 +/- 16 percent six months after transplantation. Five early deaths (within one month) were due to hemorrhage (in one patient), acute lung injury (in three), and dehiscence of the bronchial anastomosis (in one). Eleven late deaths (after one month) were due to infections (in eight patients), bronchiolitis obliterans (in two), and metastatic nephroblastoma (in one). Disease-associated problems were extensive pleural adhesions in 18 patients, leading to moderate-to-severe intraoperative hemorrhage in 4; pneumothorax in the native lung after single-lung transplantation in 6 patients; postoperative chylothorax in 3; and recurrent lymphangioleiomyomatosis in the allograft in 1 patient, who died of disseminated aspergillosis. CONCLUSIONS Although disease-related complications are frequent, lung transplantation can be a valuable therapy for patients with end-stage lymphangioleiomyomatosis.

Pulmonary Arterial Hypertension Related to HIV Infection: Improved Hemodynamics and Survival Associated with Antiretroviral Therapy

This study aimed to assess the long-term course of pulmonary arterial hypertension related to infection with human immunodeficiency virus (PAHRH) and the influence of antiretroviral therapy (ART) on its characteristics. We retrospectively analyzed all 47 patients in the Swiss HIV Cohort Study in whom PAHRH was diagnosed. Among 35 patients who underwent follow-up Doppler echocardiography, the right ventricular systolic pressure over right atrial pressure gradient increased by a median of 25 mm Hg in 9 patients who had not received ART, decreased by a median of 3 mm Hg in 12 patients who had received nucleoside analogs, and decreased by a median of 21 mm Hg in 14 patients who had received highly active ART (HAART) (P<.005). Among all 47 patients, median duration of survival after PAHRH diagnosis was 2.7 years. HAART significantly decreased mortality due to PAHRH as well as other causes. This study suggests a beneficial effect of combination ART in patients with PAHRH.

Anticoagulation and Survival in Pulmonary Arterial Hypertension Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA)

Background— For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). Methods and Results— We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival (P=0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (P=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. Conclusions— The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01347216.BACKGROUND: For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We analyzed data from COMPERA, an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1,283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year-survival (p=0.006) in patients on anticoagulation compared to patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (p=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio 0.79, 95% confidence interval 0.66 to 0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. CONCLUSIONS: The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. CLINICAL TRIALS REGISTRATION INFORMATION: www.clinicaltrials.gov. Identifier: NCT01347216.

Safety and efficacy of exercise training in various forms of pulmonary hypertension

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.

Measurement of quality of life in pulmonary hypertension and its significance.

Until recently, assessment of patients with pulmonary hypertension has mainly relied on functional and haemodynamic parameters. Health-related quality of life (HRQOL), however, has become increasingly important in defining overall health status. The present study investigated the performance and clinical relevance of the Minnesota Living with Heart Failure (MLHF) questionnaire by prospectively studying 48 patients with either pulmonary arterial hypertension (n = 26) or chronic thromboembolic pulmonary hypertension (n = 22). The MLHF scores were correlated to various clinical and haemodynamic parameters. Prognostic outcome was evaluated by calculating the time taken to reach an adverse clinical event defined as death, lung transplantation or pulmonary endarterectomy. The reliability of test–re-test and internal consistency of this HRQOL tool was high. The MLHF score and its physical subscore correlated moderately to well with functional and haemodynamic parameters, except in the case of pulmonary artery pressures. Both scores significantly improved during vasodilator therapy. This figure was surpassed only by the New York Heart Association/World Health Organization functional class. A multivariate analysis of all variables revealed that the MLHF score was the sole factor predicting subsequent outcome. The Minnesota Living with Heart Failure questionnaire is highly reproducible, consistent, and a moderately valid and responsive tool in assessing health-related quality of life in pulmonary hypertension. Moreover, it is a significant predictor of outcome in these patients.

Anticoagulation and Survival in Pulmonary Arterial Hypertension

Background— For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). Methods and Results— We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival (P=0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (P=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. Conclusions— The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01347216.BACKGROUND: For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We analyzed data from COMPERA, an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1,283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year-survival (p=0.006) in patients on anticoagulation compared to patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (p=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio 0.79, 95% confidence interval 0.66 to 0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. CONCLUSIONS: The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. CLINICAL TRIALS REGISTRATION INFORMATION: www.clinicaltrials.gov. Identifier: NCT01347216.

Epidemiology and Management of Infections after Lung Transplantation

Lung transplantation has become an accepted treatment for end-stage pulmonary parenchymal and vascular diseases. Infections still are the most common cause of early and late morbidity and mortality in lung transplant recipients. Bacterial infections comprise approximately half of all infectious complications. Cytomegalovirus (CMV) infections and disease have become less frequent, because of prophylaxis with ganciclovir. Because CMV is also involved in the pathogenesis of obliterative bronchiolitis, the frequency of this infection may also reduce the occurrence of this main obstacle to successful lung transplantation. Invasive fungal infections remain a problem, but they have also decreased in frequency because of better control of risk factors such as CMV disease and preemptive antifungal therapy. Nonherpes respiratory viral infections have emerged as a serious problem. Their severity may be reduced by treatment with ribavirin. Meticulous postoperative surveillance, however, is still crucial for the management of lung transplant patients with respect to early detection and treatment of rejection and infection.

Extracorporeal Photopheresis After Lung Transplantation : A 10-Year Single-Center Experience

We report the largest single-center experience with extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) and recurrent acute rejection (AR) after lung transplantation. Lung transplant recipients undergoing ECP for BOS and recurrent AR were included (1997-2007). The rate of forced expiratory volume in 1 second (FEV1) decline was used as the primary measure and graft survival post-ECP as the secondary measure of efficacy. Twenty-four transplant recipients were included (BOS, n=12; recurrent AR, n=12). In recipients with BOS, decline in FEV1 was 112 mL/month before the start of ECP and 12 mL/month after 12 ECP cycles (P=0.011), mean (95% CI) change in rate of decline was 100 (28-171). Median patient survival was 7.0 (range, 3.0-13.6) years, median patient survival post-ECP 4.9 (range, 0.5-8.4) years. No ECP-related complications occurred. Extracorporeal photopheresis reduces the rate of lung function decline in recipients with BOS and is well tolerated. Furthermore, recipients with recurrent AR experience clinical stabilization. However, the underlying mechanism of ECP remains subject to further research.

Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients.

Background. There are no data on the effects of mycophenolate mofetil (MMF) on the incidence of bronchiolitis obliterans syndrome (BOS) in lung-transplant patients. This study attempted to determine whether MMF reduces the incidence of BOS in de novo lung transplant recipients compared with azathioprine (AZA). Methods. This prospective, randomized, open-label, multicenter study compared the effects of MMF with AZA in combination with induction therapy, cyclosporine (Neoral) and corticosteroids in patients receiving their first lung transplant. Primary endpoint was incidence of BOS at 3 years. Secondary endpoints were incidence of acute rejection, time to first rejection event, and survival. Results. The incidence of acute rejection and the time to first rejection event at 1 and 3 years did not differ between groups (54.1% vs. 53.8% and 56.6% vs. 60.3% for MMF and AZA respectively). Survival at 1 year tended to be better in patients receiving MMF (88 vs. 80%, P=0.07). At year 3, there was no difference in survival or in the incidence, severity or time to acquisition of BOS between the two groups. Treatment was generally well tolerated, however more patients withdrew from AZA treatment than from MMF (59.6% vs. 46.5%, P=0.02). As a result, there was an imbalance in the observation times of the two groups (876±395 vs. 947±326 days). Conclusions. No differences were seen in the incidence of acute rejection or BOS in lung transplant recipients treated with MMF or AZA. This null result may have been influenced by the shorter observation time for AZA patients.