Rudolf Speich’s research while affiliated with University of Zurich and other places

Zusammenfassung Im Zeitalter der hochtechnisierten Medizin werden Anamnese und klinische Untersuchung zunehmend in den Hintergrund gedrängt. Es ist aber eine Tatsache, dass damit auch heute noch 80 % aller Diagnosen gestellt werden können. Vielfach dienen weitere, zumeist apparative Tests nur noch der Bestätigung der Diagnose. Eine kompetente Anamnese und klinische Untersuchung machen nicht selten teure und/oder zeitaufwendige Explorationen unnötig. Vor allem gilt es zu betonen, dass die aufgrund des klinischen Eindrucks gewonnene subjektive Einschätzung der Vortestwahrscheinlichkeit für das Vorliegen einer Krankheit eine unabdingbare Voraussetzung für die Bewertung weiterer Testresultate ist.

Background: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. Methods: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm(5) and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. Findings: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70-0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). Interpretation: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. Funding: Actelion Pharmaceuticals Ltd.

Background: The significance of pulmonary hypertension (PH) on exercise in systemic sclerosis (SSc) is unknown. Aims and objectives: To study outcome of SSc with exercise vs. resting PH. Methods: Exercise right heart catheters (RHC) from SSc from 2005-15 were retrospectively analyzed along with NYHA, 6 minute walk distance (6MWD) and transplant-free survival. Results: Exercise RHC of 84 patients (72 females) median (quartiles) age 62 (51;75), NYHA 2 (2;3), FVC 90 (81;105) %pred., DLCO 58 (43;64) %pred. were analyzed. 17 had resting- (restPH), 28 exercise precapillary PH (ΔmPAP/ΔCO>3mmHg/l/min & mPAP≥30mmHg, exPH) and 10 exercise postcapillary PH (Wedge>20mmHg). Patients with restPH achieved a lower workload than patients with exPH or without PH (20 (15;30) vs. 30 (30;40) resp. 30 (20;40) watts, p= 0.043). The pressure-flow ratio was lowest without PH 3.7 (1.9;7.9) intermediate in exPH 8.3 (6.1;30) and highest in restPH 24 (12.6;82.2) mmHg/l/min (p=0.000 restPH or exPH vs. no PH, p=0.027 restPH vs. exPH). All patients with restPH and 16/28 with exPH received PH-therapy for at least 3 months. Patients with restPH had an improved NYHA at 3months. During 1167±878 days, 12 patients died and 2 were transplanted. Transplant-free survival was better in patients without PH compared to patients with restPH or exPH (p=0.019 or 0.48) but was similar for treated vs. untreated exPH. Conclusions: SSc patients with restPH, but also precapillary exPH have worse transplant free survival compared with SSc without PH. The increased pressure/flow-ratio during exercise in SSc with exPH may suggest early pulmonary vascular disease for which treatment might be considered if confirmed by randomized trials.

Background: Pulmonary hypertension (PH) leads to reduced health-related quality of life (HRQoL). Objective: To investigate the prevalence and course of anxiety and depression and their association with HRQoL, disease severity and survival in PH. Methods: 131 PH patients (91 pulmonary arterial, 30 chronic thromboembolic, 10 due to lung disease; 84 female, 47 male) had repeated assessments with the Hospital Anxiety and Depression Scale (HADS), HRQoL, six-minute walk distance and WHO functional class during a mean course of 16 ± 12 months. Results: Among the 49 incident and 82 prevalent PH patients, the HADS score was positive in 53%/21% (depression), 51%/24% (anxiety) and 63%/26% (total score) (all p < 0.05). The HADS score was improved at the second assessment in incident patients. The HADS score correlated with HRQoL at all consecutive assessments and with functional class until the third assessment, but not with baseline hemodynamics, age or gender. Conclusion: Mood disorders remain underdiagnosed in PH. The higher prevalence of anxiety/depression in incident versus prevalent patients and the improvement over time may indicate an amelioration of mood disorders after PH diagnosis and treatment.

Chronic thromboembolic pulmonary hypertension, a rare complication of acute pulmonary embolism, is characterized by fibrothrombotic obstructions of large pulmonary arteries combined with small-vessel arteriopathy. It can be cured by pulmonary endarterectomy, and can be clinically improved by medical therapy in inoperable patients. A European registry was set up in 27 centers to evaluate long-term outcome and outcome correlates in 2 distinct populations of operated and not-operated patients who have chronic thromboembolic pulmonary hypertension. Methods and Results-A total of 679 patients newly diagnosed with chronic thromboembolic pulmonary hypertension were prospectively included over a 24-month period. Estimated survival at 1, 2, and 3 years was 93% (95% confidence interval [CI], 90-95), 91% (95% CI, 87-93), and 89% (95% CI, 86-92) in operated patients (n=404), and only 88% (95% CI, 83-91), 79% (95% CI, 74-83), and 70% (95% CI, 64-76) in not-operated patients (n=275). In both operated and not-operated patients, pulmonary arterial hypertension-targeted therapy did not affect survival estimates significantly. Mortality was associated with New York Heart Association functional class IV (hazard ratio [HR], 4.16; 95% CI, 1.49-11.62; P=0.0065 and HR, 4.76; 95% CI, 1.76-12.88; P=0.0021), increased right atrial pressure (HR, 1.34; 95% CI, 0.95-1.90; P=0.0992 and HR, 1.50; 95% CI, 1.20-1.88; P=0.0004), and a history of cancer (HR, 3.02; 95% CI, 1.36-6.69; P=0.0065 and HR, 2.15; 95% CI, 1.18-3.94; P=0.0129) in operated and not-operated patients, respectively. Additional correlates of mortality were bridging therapy with pulmonary arterial hypertension-targeted drugs, postoperative pulmonary hypertension, surgical complications, and additional cardiac procedures in operated patients, and comorbidities such as coronary disease, left heart failure, and chronic obstructive pulmonary disease in not-operated patients. Conclusions-The long-term prognosis of operated patients currently is excellent and better than the outcome of notoperated patients.

Background: Pulmonary hypertension manifests with impaired exercise capacity. Our aim was to investigate whether mean pulmonary arterial pressure to cardiac output relationship (mPAP/CO) predict transplant-free survival in pulmonary arterial and inoperable chronic thromboembolic pulmonary hypertension (PAH and CTEPH). Methods: Hemodynamic data by right heart catheter in PAH and CTEPH patients at rest and during supine incremental cycle exercise were analyzed. Transplant-free-survival and predictive value of hemodynamics were assessed by Kaplan-Meier and Cox-regression-analysis. Results: 70 patients (43 female, 54 PAH, 16 CTEPH; median (quartiles) age 65(50;73) years, mPAP 34(29;44) mmHg, cardiac index (CI) 2.8(2.3;3.5) (l/min)/m(2) were followed 610(251;1256) days. 1, 3, 5, 7-year survival was 89, 80, 71, 59 %. Age, WHO-functional class, 6-minute-walk distance and mixed-venous SO2 but not resting hemodynamics predicted transplant-free-survival. Maximal workload (hazard ratio, 95%-CI; p-value: 0.94(0.89-0.99); 0.027), peak and change in CI (0.51(0.27-0.95);0.034 and 0.25(0.06-0.94); 0.040) and mPAP/CO (1.02(1.01-1.03); 0.003) during exercise predicted survival. mPAP/CO predicted 3-year transplant-free-survival with an area under the curve of 0.802 (95%-CI: 0.66-0.95, p=0.004). Conclusions: In this collective of patients with PAH or CTEPH, pressure-flow-relationship during exercise predicted transplant-free-survival and correlated with established markers of disease severity and prognosis. Exercise right heart catheterization may provide important complementary prognostic information in the management of PH.