Jürgen Wellmann

Meta-Analysis of the Efficacy of Granulocyte-Colony Stimulating Factor in Animal Models of Focal Cerebral Ischemia

Background and Purpose— Recent reports have described the efficacy of the hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) in animal stroke models. Early clinical multicenter trials evaluating the effect of G-CSF in acute stroke and pilot clinical trials for the subacute phase are ongoing. To guide further development, a meta-analysis was performed to assess the effects of G-CSF on infarct size and sensorimotor deficits. Methods— Using electronic and manual searches of the literature, we identified studies describing the efficacy of G-CSF in animal models of focal cerebral ischemia. Two reviewers independently selected studies and extracted data on study quality, G-CSF doses, time of administration, and outcome measured as infarct volume and/or sensorimotor deficit. Data from all studies were pooled by meta-regression analyses. Results— Thirteen studies including 277 animals for infarct size calculation and 258 animals for assessment of sensorimotor deficit met the criteria for inclusion. Overall efficacy of G-CSF regarding infarct size reduction was 42%. Meta-regression analysis revealed a 0.8% (P<0.0001) decrease in infarct size per 1-&mgr;g/kg increase in G-CSF dose when applied within the first 6 hours and a 2.1% (P<0.0001) decrease when applied later than 6 hours after induction of ischemia with a significant (P=0.0004) greater infarct size reduction after delayed treatment. Sensorimotor deficits categorized into 3 subgroups improved between 24% and 40%. Conclusions— Our findings consolidate G-CSF as a drug that both reduces infarct size and enhances functional recovery. These effects are presumably dose dependent. In contrast to most other neuroprotectants, a beneficial outcome may also be achieved when treatment is delayed.

Blood pressure control and knowledge of target blood pressure in coronary patients across Europe: results from the EUROASPIRE III survey.

Background Blood pressure management is a key issue among patients with coronary heart disease (CHD). The present study aimed to identify particular patient groups that may need to be specifically targeted in secondary prevention of CHD. Methods EUROASPIRE III is a cross-sectional study conducted in 2006–2007 among patients up to 80 years of age hospitalized for CHD. Patients from 76 centres in 22 European regions were examined on average 15 months after hospitalization. Logistic regression analysis was applied to investigate factors associated with blood pressure control and knowledge of target blood pressure using the cut-point of less than 140/90 mmHg. Results Among 7649 patients using antihypertensive medication 50.4% achieved blood pressure control and 49.4% provided accurate knowledge of target blood pressure. Obese patients were less likely to show controlled blood pressure [odds ratio (OR) 0.72, 95% confidence interval (CI) 0.65–0.80] and accurate knowledge of blood pressure target values (OR 0.80, 95% CI 0.72–0.90). Dyslipidaemia was negatively associated with blood pressure control and accurate target knowledge. Patients with diabetes mellitus less frequently achieved blood pressure control (OR 0.89, 95% CI 0.79–0.99). Accurate knowledge of target blood pressure was positively related to blood pressure control (OR 1.12, 95% CI 1.00–1.24). Patients who received advice by a health professional to reduce salt intake, to reduce weight, and to increase physical activity more frequently showed accurate knowledge of blood pressure target values. Conclusion Blood pressure control and knowledge of target blood pressure are inappropriate in the European high-risk population of coronary patients. Particularly CHD patients with obesity, diabetes, and dyslipidaemia need better management and control of elevated blood pressure.

Recent trends in morbidity and in-hospital outcomes of in-patients with peripheral arterial disease: a nationwide population-based analysis

AIMS The prevalence of peripheral arterial disease (PAD) and especially of critical limb ischaemia (CLI) is announced to rise dramatically worldwide, with a considerable impact on the health care and socio-economic systems. We aimed to characterize the recent trends in morbidity and in-hospital outcome of PAD among all hospitalized patients in the entire German population between 2005 and 2009. METHODS AND RESULTS Nationwide data of all hospitalizations in Germany in 2005, 2007, and 2009 were analysed regarding the prevalence of PAD, comorbidities, endovascular (EVR) and surgical revascularizations (SR), major and minor amputations, in-hospital mortality, and associated costs. From 2005 to 2009, total PAD cases increased by 20.7% (from 400 928 to 483 961), with an increase of CLI subset from 40.6 to 43.5%. Total EVR increased by 46%, while thromb-embolectomy, endarterectomy, and patch plastic increased by 67, 42, and 21%, respectively. Peripheral bypasses decreased by 2%. Major amputation decreased from 4.6 to 3.5%, while minor amputation slightly increased from 4.98 to 5.11%. The crude overall in-hospital mortality remained unchanged in claudicants (2.2%), while it decreased from 9.8 to 8.4% in CLI patients. However, mortality rate according to the Poisson model (n/1000 hospital residence days) increased significantly in claudicants (P < 0.001). Total reimbursement costs for PAD in-patient care increased by 21% with an average per case costs in 2009 of €4506 in a claudicant and €6791 in a CLI patient. CONCLUSION This population-based analysis documents the significant rise of PAD, particularly of the CLI subset, and highlights the malign prognosis associated with PAD as indicated by high amputation and in-hospital mortality rates.

The Efficacy of Erythropoietin and Its Analogues in Animal Stroke Models. A Meta-Analysis

Background and Purpose— Erythropoietin (EPO) was explored regarding its suitability as a candidate stroke drug in animal experimental studies. We performed a meta-analysis to obtain an overall impression of the efficacy of EPO in published animal experimental stroke studies and for potential guidance of future clinical studies. Methods— By electronic and manual searches of the literature, we identified studies describing the efficacy of EPO in experimental focal cerebral ischemia. Data on study quality, EPO dose, time of administration, and outcome measured as infarct volume or functional deficit were extracted. Data from all studies were pooled by means of a meta-analysis. Results— Sixteen studies were included in the meta-analysis. When administered after the onset of ischemia, EPO and its analogues reduced infarct size by 32% and improved neurobehavioral deficits significantly. A meta-regression suggests higher doses of EPO to be associated with smaller infarct volumes. When administered earlier than 6 hours EPO was more effective compared to a later treatment initiation. Both hematopoietic and nonhematopoietic EPO analogues showed efficacy in experimental stroke. Conclusion— In conclusion, this analysis further strengthens confidence in the efficacy of EPO and its analogues in stroke therapy. Nonhematopoietic EPO analogues which are known to have less systemic adverse effects compared to EPO are also promising candidate stroke drugs. Further experimental studies are required that evaluate the safety of a combination of EPO with thrombolysis and whether EPO is also effective in animals with comorbidity.

A randomized controlled trial comparing hydration therapy to additional hemodialysis or N-acetylcysteine for the prevention of contrast medium-induced nephropathy

SummaryContrast mediuminduced nephropathy (CIN) is a serious complication with increasing frequency and an unfavorable prognosis. Previous analyses of surrogate parameters have suggested beneficial effects of hemodialysis that are assessed in this randomized clinical trial.We performed a prospective single-center trial in 424 consecutive patients with serum creatinine concentrations between 1.3– 3.5 mg/dl who underwent elective coronary angiography. Patients were randomized to one of three treatment strategies with all patients receiving pre- and postprocedural hydration: One group received no additional therapy, patients in the second group were hemodialyzed once, and the third group received oral N-acetylcysteine. The frequency of CIN (defined as an increase in serum creatinine ≥0.5 mg/dl) from 48 to 72 h after catheterization was 6.1% in the hydration-only group, 15.9% with hemodialysis treatment, and 5.3% in the N-ACC group (intention-to-treat analysis; P = 0.008). There were no differences between the treatment groups with regard to increased (≥ 0.5 mg/dl) serum creatinine concentrations after 30–60 days (4.8%, 5.1%, and 3.1%, respectively; P = 0.700). Analyses of long-term follow-up (range 63 to 1316 days) by Cox regressions models of the study groups found quite similar survival rates (P = 0.500). In contrast to other (retrospective) studies, long-term survival of patients with vs those without CIN within 72 h was not different, but patients who still had elevated creatinine concentrations at 30–60 days suffered from a markedly higher 2-year mortality (46% vs 17%, P = 0.002).In conclusion, hemodialysis in addition to hydration therapy for the prevention of CIN provided no evidence for any outcome benefit but evidence for probable harm. Increased creatinine concentrations at 30–60 days, but not within 72 h, were associated with markedly reduced long-term survival.

Changes in alcohol intake and risk of coronary heart disease and all-cause mortality in the MONICA/KORA-Augsburg cohort 1987-97

Background Most studies on the effect of alcohol consumption on coronary heart disease or all-cause mortality assess alcohol intake at one point in time and therefore do not take into consideration changes in drinking habits over time. We investigate whether a second assessment of alcohol intake substantially improves estimation of the effects of alcohol intake on these outcomes. Design A prospective cohort study of 2710 men and women, age 35-64 years at baseline in 1984/85 in the Augsburg region in southern Germany. We recorded incident fatal and non-fatal coronary events and all-cause mortality until 1997. Alcohol intake and other explanatory variables were assessed in 1984/85 and 1987/88. Methods Based on these assessments, participants were classified as non-drinkers, quitters, starters and constant drinkers. We calculated hazard rate ratios for coronary events and all-cause mortality in these groups and adjusted for several potential confounders using Coxs proportional hazards model. These estimates were compared with hazard rate ratios based on a single assessment of alcohol intake in 1987/88. Results Among male constant drinkers the adjusted hazard rate ratio (HRR) for coronary events was lowest among those consuming 0.1-19.9 g alcohol per day, compared with non-drinkers [HRR 0.29; 95% confidence interval (Cl) 0.12-0.70]. The lowest all-cause mortality risk was observed among men drinking 20.0-39.9 g per day (HRR 0.48; 95% Cl 0.26-0.88). In female constant drinkers the HRR for all-cause mortality was 0.71 (95% Cl 0.40-1.26) for those reporting 0.1-19.9 g daily alcohol consumption. Hazard rate ratios for alcohol intake classified by two assessments consistently revealed a more pronounced beneficial effect of alcohol consumption than those for alcohol intake groups based on a single measurement. Conclusions Assessment of alcohol intake at two points in time seems slightly to improve the risk estimation for coronary heart disease (CHD) and for all-cause mortality, compared with a single measurement. Thus, our findings strengthen the evidence of a beneficial effect of light to moderate alcohol consumption on coronary heart disease and all-cause mortality.

Cancer mortality in German carbon black workers 1976–98

Background: Few studies have investigated cancer risks in carbon black workers and the findings were inconclusive. Methods: The current study explores the mortality of a cohort of 1535 male German blue-collar workers employed at a carbon black manufacturing plant for at least one year between 1960 and 1998. Vital status and causes of death were assessed for the period 1976–98. Occupational histories and information on smoking were abstracted from company records. Standardised mortality ratios (SMR) and Poisson regression models were calculated. Results: The SMRs for all cause mortality (observed deaths (obs) 332, SMR 120, 95% CI 108 to 134), and mortality from lung cancer (obs 50, SMR 218, 95% CI 161 to 287) were increased using national rates as reference. Comparisons to regional rates from the federal state gave SMRs of 120 (95% CI 107 to 133) and 183 (95% CI 136 to 241), respectively. However, there was no apparent dose response relationship between lung cancer mortality and several indicators of occupational exposure, including years of employment and carbon black exposure. Conclusions: The mortality from lung cancer among German carbon black workers was increased. The high lung cancer SMR can not fully be explained by selection, smoking, or other occupational risk factors, but the results also provide little evidence for an effect of carbon black exposure.

Cancer incidence in type 2 diabetes patients - first results from a feasibility study of the D2C cohort

BackgroundA large prospective study in patients with type 2 diabetes (T2D), the German D2C cohort, is presently being enumerated to investigate risk factors of incident cancer in diabetic patients.Study settingA disease management program was offered, on a voluntary basis, to all T2D patients who were members of a statutory health insurance fund in Germany. This first feasibility report uses data from 26.742 T2D patients, who were 40 to 79 years old, resided in the Muenster District, and who were enrolled between June 2003 and July 2008. Cancer cases were identified through the regional Cancer Registry.MethodsInvasive cancer cases were identified using probabilistic record linkage procedures and pseudonymised personal identifiers. Censoring date was December 31, 2008. We included only first cancers, leaving 12.650 male and 14.092 female T2D with a total of 88.778 person-years (py). We computed standardised incidence ratios (SIR) for external comparisons and we employed Cox regression models and hazard ratios (HR) within the cohort.ResultsWe identified 759 first cancers among male T2D patients (18.7 per 1,000 py) and 605 among females (12.7 per 1,000 py). The risk of any incident cancer in T2D was raised (SIR = 1.14; 95% confidence interval [1.10 - 1.21]), in particular for cancer of the liver (SIR = 1.94 [1.15 - 2.94]) and pancreas (SIR = 1.45 [1.07-1.92]). SIRs decreased markedly with time after T2D diagnosis. In Cox models, adjusting for diabetes duration, body mass index and sex, insulin therapy was related to higher cancer risk (HR = 1.25 [1.17 - 1.33]). No effect was seen for metformin.DiscussionOur study demonstrates feasibility of record linkage between DMP and cancer registries. These first cohort results confirm previous reports. It is envisaged to enhance this cohort by inclusion of further regions of the state, expansion of the follow-up times, and collection of a more detailed medication history.

Meta-analysis of the Efficacy of Different Training Strategies in Animal Models of Ischemic Stroke

Background and Purpose— Although several studies have shown beneficial effects of training in animal stroke models, the most effective training strategy and the optimal time to initiate training have not been identified. The present meta-analysis was performed to compare the efficacy of different training strategies and to determine the optimal time window for training in animal stroke models. Methods— We searched the literature for studies analyzing the efficacy of training in animal models of ischemic stroke. Training was categorized into forced physical training, voluntary physical training, constraint-induced movement therapy, and skilled reaching training. Two reviewers independently extracted data on study quality, infarct size, and neurological outcome. Data were pooled by means of a meta-analysis. Results— Thirty-five studies with >880 animals were included. A meta-analysis of all treatments showed that training reduced the infarct volume by 14% (95% confidence interval, 2%–25%) and improved the cognitive function by 33% (95% confidence interval, 8%–50%), the neuroscore by 13.4% (95% confidence interval, 1.5%–25.3%), and the running function by 6.6% (95% confidence interval, 1.4%–11.9%). Forced physical training reduced the infarct volume and enhanced the running function most effectively, whereas skilled reaching training improved the limb function most effectively. A meta-regression illustrated that training was particularly efficacious when initiated between 1 and 5 days after stroke onset. Conclusions— Our meta-analysis confirms that training reduces the infarct volume and improves the functional recovery in animal stroke models. Forced physical training and skilled reaching training were identified as particularly effective training strategies. The efficacy of training is time dependent.

Impact of the Extended Thrombolysis Time Window on the Proportion of Recombinant Tissue-Type Plasminogen Activator-Treated Stroke Patients and on Door-to-Needle Time

Background and Purpose— The European Cooperative Acute Stroke Study (ECASS) III extended the thrombolysis time window for patients with stroke from 3 to 4.5 hours after symptom onset. We investigated the effect of the extended thrombolysis time window on the proportion of recombinant tissue-type plasminogen activator-treated stroke patients and on the time of treatment initiation after hospital arrival. Methods— The present study was based on a prospective database of 93 hospitals of the Stroke Register of Northwestern Germany, which included 91 805 patients with ischemic stroke admitted between January 2007 and December 2009. Main outcome measures were the use of recombinant tissue-type plasminogen activator among patients with stroke and the door-to-needle time before and after the publication of ECASS III in September 2008 and subsequent changes of the German guidelines in May 2009. Results— Overall, 9262 patients (10.1%) were treated with recombinant tissue-type plasminogen activator. The proportion of thrombolyzed patients increased from 8.6% in 2007 to 11.7% in 2009. This increase was pronounced for patients admitted between 3 and 6 hours after symptom onset after the third quarter of 2008 (OR, 1.88; 95% CI, 1.24 to 2.85) and after the second and third quarters of 2009 (OR, 2.50; 95% CI, 1.69 to 3.69 and OR, 3.02; 95% CI, 2.07 to 4.41) compared with the first half year 2007. The proportion of patients with stroke with a door-to-needle time <60 minutes increased after publication of ECASS III (OR, 1.49; 95% CI, 1.37 to 1.63). Conclusions— Results of ECASS III were rapidly implemented in routine stroke care. Concerns of a delay in recombinant tissue-type plasminogen activator treatment initiation after the extension of the thrombolysis time window were not confirmed.