Walter Lehmacher

Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial.

BACKGROUND Organ-confined renal-cell carcinoma is associated with tumour progression in up to 50% of patients after radical nephrectomy. At present, no effective adjuvant treatment is established. We aimed to investigate the effect of an autologous renal tumour cell vaccine on risk of tumour progression in patients with stage pT2-3b pN0-3 M0 renal-cell carcinoma. METHODS Between January, 1997, and September, 1998, 558 patients with a renal tumour scheduled for radical nephrectomy were enrolled at 55 institutions in Germany. Before surgery, all patients were centrally randomised to receive autologous renal tumour cell vaccine (six intradermal applications at 4-week intervals postoperatively; vaccine group) or no adjuvant treatment (control group). The primary endpoint of the trial was to reduce the risk of tumour progression, defined as progression or death. All patients were assessed after standardised diagnostic investigations at 6-month intervals for a minimum of 4.5 years. FINDINGS By preoperative and postoperative inclusion criteria, 379 patients were assessable for the intention-to-treat analysis. At 5-year and 70-month follow-up, the hazard ratios for tumour progression were 1.58 (95% CI 1.05-2.37) and 1.59 (1.07-2.36), respectively, in favour of the vaccine group (p=0.0204, log-rank test). 5-year and 70-month progression-free survival rates were 77.4% and 72%, respectively, in the vaccine group and 67.8% and 59.3%, respectively, in the control group. The vaccine was well tolerated, with only 12 adverse events associated with the treatment. INTERPRETATION Adjuvant treatment with autologous renal tumour cell vaccine in patients with renal-cell carcinoma after radical nephrectomy seems to be beneficial and can be considered in patients undergoing radical nephrectomy due to organ-confined renal-cell carcinoma of more than 2.5 cm in diameter.

Correlation between BMI, leisure habits and motor abilities in childhood (CHILT-Project)

INTRODUCTION: The prevalence of childhood obesity is increasing with its negative medical and psychosocial consequences. This paper examines the association between body mass index (BMI), motor abilities and leisure habits of 668 children within the CHILT (Childrens Health InterventionaL Trial) project.APPROACH: A total of 668 children (51.0% boys; 49.0% girls) and their parents were questioned on sport and leisure behaviour of the children. The anthropometric data were measured. Motor abilities were determined by a body gross motor development test for children (Köperkoordinationstest für Kinder; KTK) and a 6-min run.RESULTS: The children were 6.70±0.42 y old, 122.72±5.36 cm tall and weighed 24.47±4.59 kg, the average BMI was 16.17±2.27 kg/m2. KTK showed an average motor quotient (MQ) of 93.49±15.01, the 6-min run an average of 835.24±110.87 m. Both tests were inversely correlated with BMI (KTK and BMI r=−0.164 (P<0.001); 6-min run and BMI r=−0.201 (P<0.001)); the group of overweight/obese children showed poorer results than the normal/underweight ones, even after adjustment for gender and age (in each case P<0.001). Children with the greatest extent of exercise achieve the highest MQ (P=0.035).SUMMARY: Overweight/obesity is associated with a poorer body gross motor development and endurance performance. On the other hand, an active lifestyle is positively correlated with a better gross motor development in first-grade children. Therefore, to prevent the negative consequences of physical inactivity and overweight/obesity early intervention to support exercise and movement is recommended.

Safety and Efficacy of Enoxaparin Compared With Unfractionated Heparin and Oral Anticoagulants for Prevention of Thromboembolic Complications in Cardioversion of Nonvalvular Atrial Fibrillation The Anticoagulation in Cardioversion using Enoxaparin (ACE) Trial

Background—Anticoagulation in cardioversion of atrial fibrillation is currently performed with unfractionated heparin (UFH) and oral anticoagulants, with or without guidance by transesophageal echocardiography (TEE). Low-molecular-weight heparins may reduce the risk of bleeding, may obviate the need for intravenous access, and do not require frequent anticoagulation monitoring. Methods and Results—In a randomized, prospective multicenter trial, we compared the safety and efficacy of enoxaparin administered subcutaneously with intravenous UFH followed by the oral anticoagulant phenprocoumon in 496 patients scheduled for cardioversion of atrial fibrillation of >48 hours’ and ≤1 year’s duration. Patients were stratified to cardioversion with (n=431) and without (n=65) guidance by TEE. The study aimed to demonstrate noninferiority of enoxaparin compared with UFH+phenprocoumon with regard to the incidence of embolic events, all-cause death, and major bleeding complications. Secondary end points included successful cardioversion, maintenance of sinus rhythm until study end, and minor bleeding complications. Of 496 randomized patients, 428 were analyzed per protocol. Enoxaparin was noninferior to UFH+phenprocoumon with regard to the incidence of the composite primary end point in a per-protocol analysis (7 of 216 patients versus 12 of 212 patients, respectively; P =0.016) and in an intention-to-treat analysis (7 of 248 patients versus 12 of 248 patients, respectively; P =0.013). There was no significant difference between the 2 groups in the number of patients reverted to sinus rhythm. Conclusions—Enoxaparin is noninferior to UFH+phenprocoumon for prevention of ischemic and embolic events, bleeding complications, and death in TEE-guided cardioversion of atrial fibrillation. Its easier application and more stable anticoagulation may make it the preferred drug for initiation of anticoagulation in this setting.

Lipoprotein Apheresis in Patients With Maximally Tolerated Lipid-Lowering Therapy, Lipoprotein(a)-Hyperlipoproteinemia, and Progressive Cardiovascular Disease Prospective Observational Multicenter Study

Background— Lipoprotein(a) (Lp(a)) hyperlipoproteinemia is a major risk factor for cardiovascular disease, which is not affected by treatment of other cardiovascular risk factors. This study sought to assess the effect of chronic lipoprotein apheresis (LA) on the incidence of cardiovascular events in patients with progressive cardiovascular disease receiving maximally tolerated lipid-lowering treatment. Methods and Results— In a prospective observational multicenter study, 170 patients were investigated who commenced LA because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease. Patients were characterized regarding plasma lipid status, lipid-lowering drug treatment, and variants at the LPA gene locus. The incidence rates of cardiovascular events 2 years before (y-2 and y-1) and prospectively 2 years during LA treatment (y+1, y+2) were compared. The mean age of patients was 51 years at the first cardiovascular event and 57 years at the first LA. Before LA, mean low-density lipoprotein cholesterol and Lp(a) were 2.56±1.04 mmol·L−1 (99.0±40.1 mg·dL−1) and Lp(a) 3.74±1.63 µmol·L−1 (104.9±45.7 mg·dL−1), respectively. Mean annual rates for major adverse coronary events declined from 0.41 for 2 years before LA to 0.09 for 2 years during LA (P<0.0001). Event rates including all vascular beds declined from 0.61 to 0.16 (P<0.0001). Analysis of single years revealed increasing major adverse coronary event rates from 0.30 to 0.54 (P=0.001) for y-2 to y-1 before LA, decline to 0.14 from y-1 to y+1 (P<0.0001) and to 0.05 from y+1 to y+2 (P=0.014). Conclusions— In patients with Lp(a)-hyperlipoproteinemia, progressive cardiovascular disease, and maximally tolerated lipid-lowering medication, LA effectively lowered the incidence rate of cardiovascular events. Clinical Trial Registration— URL: https://drks-neu.uniklinik-freiburg.de. Unique identifier: DRKS00003119.

Inference on multiple endpoints in clinical trials with adaptive interim analyses

Planned interim analyses which permit early stopping or sample size adaption of a trial are desirable for ethical and scientific reasons. Multiple test procedures allow inference about several hypotheses within a single clinical trial. In this paper, a method which combines multiple testing with adaptive interim analyses whilst controlling the experimentwise error rate is proposed. The general closed testing principle, the situation of a priori ordered hypotheses, and application of the Bonferroni-Holm method are considered. The practical application of the method is demonstrated by an example.

Factors which provoke post-infarction depression: Results from the post-infarction late potential study (PILP)

Symptoms of depression in the majority of patients immediately following acute myocardial infarctions (AMI) resolve rapidly; they are an adjustment reaction. However, in a group of 552 male patients there were 80 (14.5%) patients with persistent major depressive symptoms during a finite period after AMI. Infarction size was assessed by maximum creatine kinase levels, the QRS-complex and the occurrence of late potentials. These measures did not correlate with the degree of depressed moods in these groups. An arrhythmic event in the early hospitalization phase, a recurrent infarction, dyspnoea, and persistent angina pectoris before the AMI were significantly related to more profound degrees of depression. Patients who reported serious life-events in the last 2 yr before AMI, or who suffered from exhaustion and fatigue in the prehospital phase were subject to significantly higher levels of depression. A prodromal phase prior to hospitalization free of bodily symptoms and the use of denial were related to low levels of depression. The logistic regression model incorporating all univariate significant variables revealed that symptoms of exhaustion and fatigue prior to AMI had the strongest independent correlation with post AMI depression.

Impact of a New Conduction Defect After Transcatheter Aortic Valve Implantation on Left Ventricular Function

OBJECTIVES This study sought to evaluate the impact of new conduction defects after transcatheter aortic valve implantation (TAVI) on the evolution of left ventricular (LV) function during 1-year follow-up. BACKGROUND New left bundle branch block (LBBB) or need for permanent pacing due to atrioventricular (AV) block are frequent after TAVI. METHODS A total of 90 consecutive patients treated with TAVI and who had 12-month echocardiographic follow-up were included in the study. In 39 patients, a new conduction defect (new LBBB or need for permanent pacemaker activity.) persisted 1 month after TAVI. In 51 patients, no persistent new conduction defect was observed. Two-dimensional echocardiography using parasternal short-axis, apical 4-chamber, and apical 2-chamber views was performed before TAVI and at 1-year follow-up to determine LV volumes and ejection fraction based on Simpsons rule. Speckle-tracking echocardiography was applied using standard LV short-axis images to assess the effect of new conduction defects on time-to-peak radial strain of different LV segments as a parameter of LV dyssynchrony. RESULTS New conduction defects resulted in marked heterogeneity in time-to-peak strain between the 6 analyzed short-axis segments. During 1-year follow-up after TAVI, there was a significant increase in left ventricular ejection fraction (LVEF) in patients without new LBBB (53 ± 11% pre TAVI to 59 ± 10% at follow-up; p < 0.001), whereas there was no change in LVEF in patients with a new conduction defect (52 ± 11% pre TAVI to 51 ± 12% at follow-up, p = 0.740). Change in LV end-systolic volume was also significantly different between patient groups (-1.0 ± 14.2 vs. -11.2 ± 15.7 ml, p = 0.042). New conduction defect and LVEF at baseline were independent predictors of reduced LVEF at 12-month follow-up after TAVI. CONCLUSIONS LVEF improves after TAVI for treatment of severe aortic stenosis in patients without new conduction defects. In patients with a new conduction defect after TAVI, there is no improvement in LVEF at follow-up.

Analysis of Procedural Effects of Percutaneous Edge-to-Edge Mitral Valve Repair by 2D and 3D Echocardiography

Background—Analysis of procedural effects in patients undergoing percutaneous mitral valve repair (PMVR) using the edge-to-edge technique is complex, and common methods to define mitral regurgitation severity based on 2-dimensional (2D) echocardiography are not validated for postprocedural double-orifice mitral valve. This study used 3D transesophageal echocardiography (TEE) to determine the functional and morphological effects of PMVR. Methods and Results—In 39 high-risk surgical patients with moderate to severe functional mitral valve regurgitation, 3D TEE with and without color Doppler as well as 2D transthoracic and TEE was performed before and after PMVR (MitraClip device). Mitral valve regurgitant volume by color Doppler 3D TEE was determined as the product of vena contracta areas defined by direct planimetry and velocity time integral using continuous-wave Doppler. Regurgitant volume was reduced from 84.1±38.3 mL preintervention to 35.6±25.6 mL postintervention. Patients in whom vena contracta area could be reduced >50% had a smaller preprocedural mitral annulus area compared with patients with ⩽50% reduction (11.9±3.9 versus 16.1±8.5 cm2, respectively; P=0.036) and tended to have a smaller mitral annulus circumference (13.0±2.0 versus 14.8±4.1 cm, respectively; P=0.112). At 6 months follow-up, left atrial and left ventricular end-diastolic volumes were significantly more reduced in patients in whom regurgitant vena contracta area was reduced by >50% compared with those with less reduction (−11.4±5.2 versus −4.8±7.7%; P=0.005, and −11.0±7.2 versus −4.5±9.3%; P=0.028). The maximum diastolic mitral valve area decreased from 6.0±2.0 to 2.9±0.9 cm2 (P<0.0001). Conclusions—Three dimensional TEE demonstrates significant reduction of regurgitant volume after PMVR. The unique visualization of the mitral valve by 3D TEE allows improved understanding of the morphological and functional changes induced by PMVR.

Comparison of Two- and Three-Dimensional Transthoracic Echocardiography to Cardiac Magnetic Resonance Imaging for Assessment of Paravalvular Regurgitation After Transcatheter Aortic Valve Implantation

This study evaluated 2-dimensional (2D) transthoracic echocardiography (TTE) using Valve Academic Research Consortium-2 (VARC-2) criteria and 3-dimensional (3D) TTE for assessment of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) in comparison with cardiac magnetic resonance (CMR) imaging. In 71 patients, 2D TTE, 3D TTE, and CMR imaging were performed to assess AR severity after TAVI. Using 2D TTE, AR severity was graded according to VARC-2 criteria and regurgitant volume (RVol) was determined. Three-dimensional color Doppler TTE allowed direct planimetry of the vena contracta area of the paravalvular regurgitation jet and calculation of the RVol as product with the velocity-time integral. RVol by CMR imaging was measured by phase-contrast velocity mapping in the ascending aorta. After TAVI, mean RVol determined by CMR imaging was 9.2 ± 9.6 ml/beat and mean regurgitant fraction was 13.3 ± 10.3%. AR was assessed as none or mild in 58 patients (82%) by CMR imaging. Correlation of 3D TTE and CMR imaging on RVol was better than correlation of 2D TTE and CMR imaging (r = 0.895 vs 0.558, p <0.001). There was good agreement between RVol by CMR imaging and by 3D TTE (mean bias = 2.4 ml/beat). Kappa on grading of AR severity was 0.357 between VARC-2 and CMR imaging versus 0.446 between 3D TTE and CMR imaging. Intraobserver variability for analysis of RVol of AR after TAVI was 73.5 ± 52.2% by 2D TTE, 16.7 ± 21.9% by 3D TTE, and 2.2 ± 2.0% by CMR imaging. In conclusion, 2D TTE considering VARC-2 criteria has limitations in the grading of AR severity after TAVI when CMR imaging is used for comparison. Three-dimensional TTE allows quantification of AR with greater accuracy than 2D TTE. Observer variability on RVol after TAVI is considerable using 2D TTE, significantly less using 3D TTE, and very low using CMR imaging.

High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy

IntroductionIn systemic sclerosis (SSc) little evidence for the effectiveness of anti-inflammatory and immunosuppressive therapy exists. The objective of this study was to determine the extent to which SSc patients are treated with corticosteroids and immunosuppressive agents.MethodsData on duration and dosage of corticosteroids and on the type of immunosuppressive agent were analyzed from 1,729 patients who were registered in the German Network for Systemic Scleroderma (DNSS).ResultsA total 41.3% of all registered SSc patients was treated with corticosteroids. Corticosteroid use was reported in 49.1% of patients with diffuse cutaneous SSc and 31.3% of patients with limited cutaneous SSc (P < 0.0001). Among patients with overlap disease characteristics, 63.5% received corticosteroids (P < 0.0001 vs. limited cutaneous SSc). A total 16.1% of the patients received corticosteroids with a daily dose ≥ 15 mg prednisone equivalent. Immunosuppressive therapy was prescribed in 35.8% of patients. Again, among those patients with overlap symptoms, a much higher proportion (64.1%) was treated with immunosuppressive agents, compared with 46.4% of those with diffuse cutaneous SSc sclerosis and 22.2% of those with limited cutaneous SSc (P < 0.0001). The most commonly prescribed drugs were methotrexate (30.5%), cyclophosphamide (22.2%), azathioprine (21.8%) and (hydroxy)chloroquine (7.2%). The use of these compounds varied significantly between medical subspecialties.ConclusionsDespite limited evidence for the effectiveness of corticosteroids and immunosuppressive agents in SSc, these potentially harmful drugs are frequently prescribed to patients with all forms of SSc. Therefore, this study indicates the need to develop and communicate adequate treatment recommendations.