Health economic consequences of optimal vs. observed guideline adherence of coronary angiography in patients with suspected obstructive stable coronary artery in Germany: a microsimulation model.

AIMS: While the number of patients with stable coronary artery disease (SCAD) is similar across European countries, Germany has the highest per capita volume of coronary angiographies (CA). This study evaluated the health economic consequences of guideline-non-adherent use of CA in patients with SCAD. METHODS AND RESULTS: As part of the ENLIGHT-KHK trial, a prospective observational study, this microsimulation model compared the number of major adverse cardiac events (MACE) and the costs of real-world use of CA with those of (assumed) complete guideline-adherent use (according to the German National Disease Management Guideline 2019). The model considered non-invasive testing, CA, revascularization, MACE (30 days after CA), and medical costs. Model inputs were obtained from the ENLIGHT-KHK trial (i.e. patients' records, a patient questionnaire, and claims data). Incremental cost-effectiveness ratios were calculated by comparing the differences in costs and MACE avoided from the perspective of the Statutory Health Insurance (SHI). Independent on pre-test probability (PTP) of SCAD, complete guideline adherence for usage of CA would result in a slightly lower rate of MACE (-0.0017) and less cost (€-807) per person compared with real-world guideline adherence. While cost savings were shown for moderate and low PTP (€901 and €502, respectively), for a high PTP, a guideline-adherent process results in slightly higher costs (€78) compared with real-world guideline adherence. Sensitivity analyses confirmed the results. CONCLUSION: Our analysis indicates that improving guideline adherence in clinical practice by reducing the amount of CAs in patients with SCAD would lead to cost savings for the German SHI.

Evaluation of the guideline-adherence of coronary angiography in patients with suspected chronic coronary syndrome - Results from the German prospective multicentre ENLIGHT-KHK project.

Background: With 900'000 coronary angiographies (CA) per year, Germany has the highest annual per capita volume in Europe. Until now there are no prospective clinical data on the degree of guideline-adherence in the use of CA in patients with suspected chronic coronary syndrome (CCS) in Germany. Methods: Between January 2019 and August 2021, 458 patients with suspected CCS were recruited in nine German centres. Guideline-adherence was evaluated according to the current European Society of Cardiology and German guidelines. Pre-test probability (PTP) for CAD was determined using age, gender, and a standardized patient questionnaire to identify symptoms. Data on the diagnostic work-up were obtained from health records. Results: Patients were in mean 66.6 years old, male in 57.3 %, had known CAD in 48.4 % and presented with typical, atypical, non-anginal chest pain or dyspnoea in 35.7 %, 41.3 %, 23.0 % and 25.4 %, respectively. PTP according to the European guidelines was in mean 24.2 % (11.9 %-36.5 % 95 % CI). 20.9 % of the patients received guideline-recommended preceding non-invasive image guided testing. The use of CA was adherent to the European and German guideline recommendations in 20.4 % and 25.4 %, respectively. In multivariate-analysis, arterial hypertension and prior revascularization were predictors of guideline non-adherence. Conclusion: These are the first prospective clinical data which demonstrated an overall low degree of guideline-adherence in the use of CA in patients with suspected CCS in the German health care setting. To improve adherence rates, the availability of and access to non-invasive image guided testing needs to be strengthened. (German Clinical Trials Registry DRKS00015638 - Registration Date: 19.02.2019).

Guideline adherence in the use of coronary angiography in patients presenting at the emergency department without myocardial infarction - Results from the German ENLIGHT-KHK project.

Background: For patients with acute myocardial infarction (AMI), direct coronary angiography (CA) is recommended, while for non-AMI patients, the diagnostic work-up depends on clinical criteria. This analysis provides initial prospective German data for the degree of guideline-adherence (GL) in the use of CA on non-AMI patients presenting at the emergency department (ED) with suspected acute coronary syndrome (ACS) according to the 2015 ESC-ACS-GL. Furthermore the implications of the application of the 2020 ESC-ACS-GL recommendations were evaluated. Methods: Patient symptoms were identified using a standardized questionnaire; medical history and diagnostic work-up were acquired from health records. In accordance with the 2015 ESC-ACS-GL, CA was considered GL-adherent if intermediate risk criteria (IRC) were present or non-invasive, image-guided testing (NIGT) was pathological. Results: Between January 2019 and August 2021, 229 patients were recruited across seven centers. Patients presented with chest pain, dyspnea, and other symptoms in 66.7%, 16.2% and 17.1%, respectively, were in mean 66.3 ± 10.5 years old, and 36.3% were female. In accordance with the 2015 ESC-ACS-GL, the use of CA was GL-adherent for 64.0% of the patients. GL-adherent compared to non-adherent use of CA resulted in revascularization more often (44.5% vs. 17.1%, p < 0.001). Applying the 2020 ESC-ACS-GL, 20.4% of CA would remain GL-adherent. Conclusions: In the majority of cases, the use of CA was adherent to the 2015 ESC-ACS-GL. With regard to the 2020 and 2023 ESC-ACS-GL, efforts to expand the utilization of NIGT are crucial, especially as GL-adherent use of CA is more likely to result in revascularization.(German Clinical Trials Register DRKS00015638; https://drks.de/search/de/trial/DRKS00015638; (registration date: 19 February 2019)).

Evaluation of Guideline Adherence for Cardiac Catheterization in Patients With Presumed Obstructive Coronary Artery Disease in Germany (ENLIGHT-KHK) - A Multicentre, Prospective, Observational Study.

INTRODUCTION: The diagnosis or exclusion of obstructive stable coronary artery disease (SCAD) in clinical practice is challenging and therefore clinical guidelines provide recommendations on the use of non-invasive and invasive testing. For Germany, data obtained from the OECD and health insurances indicate a potential non-adherence to guideline-recommended diagnostic pathways. However, there is a lack of prospective and reliable evidence for appropriate use of invasive coronary angiography (CA) in Germany. OBJECTIVE: To provide evidence on the nature and extent of guideline non-adherence in patients undergoing CA with presumed obstructive SCAD in Germany and, to evaluate the clinical and economic consequences of potential deviations in guideline adherence. METHODS: ENLIGHT-KHK is a multicentre, prospective observational study recruiting 1500 patients being admitted for CA with presumed obstructive SCAD and exclusion of acute myocardial infarction (DRKS00015638). The primary outcome measure is the adherence to clinical guidelines in the decision-making process for use of CA. Therefore, the patients' diagnostic pathways and adherence to German and European guidelines will be assessed using clinical data, health-claims data, and a patient questionnaire. The primary safety outcome is a composite of myocardial infarction, stroke and all-cause death. Secondary outcome measures are periprocedural complications and costs. Using a decision-analytic model, the clinical and economic impact of observed guideline adherence in clinical practice will be assessed. Potential barriers and facilitators of guideline-adherent decision-making will be evaluated via semi-structured interviews. CONCLUSIONS: ENLIGHT-KHK will give insights into the appropriateness of invasive CA in Germany and enable the development of concepts to improve guideline-adherence in the German health-care setting.

Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin.

Pilocytic astrocytomas (PAs) are the most common glioma in children. Whereas many PAs are slow-growing or clinically indolent, others exhibit more aggressive features with tumor recurrence and death. To identify genetic signatures that might predict PA clinical behavior, we did gene expression profiling on 41 primary PAs arising sporadically and in patients with neurofibromatosis type 1 (NF1). Whereas no expression signature was found that could discriminate clinically aggressive or recurrent tumors from more indolent cases, PAs arising in patients with NF1 did exhibit a unique gene expression pattern. In addition, we identified a gene expression signature that stratified PAs by location (supratentorial versus infratentorial). Lastly, we also identified a gene expression pattern common to PAs and normal mouse astrocytes and neural stem cells from these distinct brain regions as well as a gene expression pattern shared between PAs and another human glial tumor (ependymoma) arising supratentorially compared with those originating in the posterior fossa. These results suggest that glial tumors share an intrinsic, lineage-specific molecular signature that reflects the brain region in which their nonmalignant predecessors originated.

Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients.

PURPOSE: Despite multimodal aggressive treatment glioblastoma patients still face a rather poor prognosis. Recent data indicate that certain molecular markers, in particular MGMT promoter hypermethylation, are associated with response to alkylating chemotherapy and longer survival. The clinical significance of other glioblastoma-associated molecular aberrations and their relationship to MGMT promoter hypermethylation is still poorly understood. EXPERIMENTAL DESIGN: We conducted a translational study involving 67 newly diagnosed glioblastoma patients treated at our institution from 1998 to 2004. All patients were treated by open resection, followed by radiotherapy and adjuvant temozolomide chemotherapy. The tumors were investigated for MGMT promoter methylation, mRNA and protein expression, as well as presence of MGMT sequence polymorphisms. In addition, we screened for genetic aberrations of the EGFR, TP53, CDK4, MDM2, and PDGFRA genes as well as allelic losses on chromosomal arms 1p, 10q, and 19q. RESULTS: Correlation of molecular findings with clinical data revealed significantly longer time to progression after onset of chemotherapy and longer overall survival of patients with MGMT-hypermethylated tumors. In contrast, MGMT protein expression, MGMT polymorphisms, and aberrations in any of the other genes and chromosomes were not significantly linked to patient outcome. Multivariate analysis identified MGMT promoter hypermethylation and near-complete tumor resection as the most important parameters associated with better prognosis. CONCLUSION: Our study provides novel insights into the significance of molecular and clinical markers in predicting the prognosis of glioblastoma patients, which may improve stratification of patients into distinct prognostic subgroups.

Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03.

PURPOSE: To evaluate toxicity and efficacy of the combination of lomustine, temozolomide (TMZ) and involved-field radiotherapy in patients with newly diagnosed glioblastoma (GBM). PATIENTS AND METHODS: Thirty-one adult patients (median Karnofsky performance score 90; median age, 51 years) accrued in two centers received involved-field radiotherapy (60 Gy in 2-Gy fractions) and chemotherapy with lomustine 100 mg/m2 (day 1) and TMZ 100 mg/m2/d (days 2 to 6) with individual dose adjustments according to hematologic toxicity. RESULTS: A median of five courses (range, one to six courses) were delivered. WHO grade 4 hematotoxicity was observed in five patients (16%) and one of these patients died as a result of septicemia. Nonhematologic toxicity included one patient with WHO grade 4 drug-induced hepatitis (leading to discontinuation of lomustine and TMZ) and one patient with WHO grade 2 lung fibrosis (leading to discontinuation of lomustine). The progression-free survival (PFS) rate at 6 months was 61.3%. The median PFS was 9 months (95% CI, 5.3 to 11.7 months), the median overall survival time (MST) was 22.6 months (95% CI, 12.5 to not assessable), the 2-year survival rate was 44.7%. O6-methylguanine-DNA methyltransferase (MGMT) gene-promoter methylation in the tumor tissue was associated with longer PFS (P = .014, log-rank test) and MST (P = .037). CONCLUSION: The combination of lomustine, TMZ, and radiotherapy had acceptable toxicity and yielded promising survival data in patients with newly diagnosed GBM. MGMT gene-promoter methylation was a strong predictor of survival.