Better lipid target achievement for secondary prevention through disease management programs for diabetes mellitus and coronary heart disease in clinical practice in Germany.

AIMS: Disease management programs (DMP) for diabetes mellitus (DM) or coronary heart disease (CHD) address the treatment of lipid disorders. The current registry aimed to compare drug utilization, lipid lowering effects and further outcomes of outpatients at high cardiovascular risk in DMP for DM or CHD compared to patients in routine care (no-DMP). METHODS: This was a prospective non-interventional registry with a 1 year follow-up which enrolled consecutive patients with known DM and/or any vascular disease on simvastatin 40 mg monotherapy, to document lipid target achievement in clinical practice in Germany according to existing guidelines. Drug use (maintenance, add-on, switch, discontinuation) and other components of care were upon the discretion of the treating physician. RESULTS: Of a total of 12,154 patients (mean age 65.8 years, 61.2% males), 3273 were in DMP CHD, 3265 in DMP DM and 1760 in DMP CHD + DM. In DMP patients compared to no-DMP patients, comorbidities/risk factors were more frequent. More patients in the DMP groups attained the target level of low density lipoprotein (LDL-C) <70 mg/dl (1.8 mmol/l) at baseline (8.5% DMP vs. 5.7% no-DMP), at 6 month (10.3% vs. 7.4%) and 12 month follow-up (10.1% vs. 7.1%). Cholesterol absorption inhibitors were added in 16% of the patients at the end of the baseline or at the follow-up visits, while statin treatment (including mean dose) remained largely unchanged. Target achievement rates were highest for all time points in the DMP CHD + DM group. With respect to limitations, this study was restricted to lipid disorders as qualifying diagnosis and simvastatin as qualifying treatment, which is a potential cause of selection bias. Information on non-pharmacological measures was not collected, and the 12-month follow-up period was relatively short. CONCLUSION: Patients in DMP compared to those not in DMP achieved better LDL-C lowering and higher control rates, but overall lipid target achievement rates need to be improved. Longer-term observations are needed to corroborate these findings.

Fractalkine promotes platelet activation and vascular dysfunction in congestive heart failure.

UNLABELLED: Endothelial dysfunction and enhanced platelet reactivity in congestive heart failure (CHF) contribute to poor prognosis. CHF patients display an impaired responsiveness to clopidogrel. Fractalkine activates platelets and elevated plasma levels of this chemokine are a feature of CHF. We here addressed the interrelation of fractalkine, platelet reactivity and clopidogrel efficacy in humans and rats with CHF. Fractalkine serum levels determined by ELISA were increased in CHF patients (CHF: 1548 ± 650 pg/ml; CONTROL: 968 ± 575 pg/ml, p<0.01) and following CHF induction in rats (CHF: 1509 ± 753 pg/ml; Sham: 1181 ± 275 pg/ml, p<0.05). Expression of fractalkine and its receptor CX3CR1 was enhanced in aortas of CHF rats as determined by immunofluorescence microscopy and molecular analysis. Fractalkine significantly aggravated endothelial dysfunction and augmented P-selectin expression on platelets from CHF rats. Platelet surface expression of CX3CR1 was increased in CHF rats, who displayed an impaired response to clopidogrel (platelet reactivity to ADP: CHF 30 ± 22%; Sham: 8 ± 5%, p<0.05). Similarly in humans with CHF, elevated fractalkine levels were accompanied by reduced clopidogrel responsiveness. Patients with high on-clopidogrel treatment platelet P2Y12 reactivity displayed higher fractalkine levels (1525 ± 487 pg/ml) than those with sufficient clopidogrel response (684 ± 315 pg/ml, p<0.01). In conclusion, in CHF fractalkine was increased on the endothelium and in blood serum, and platelet surface-expression of CX3CR1 was enhanced. Fractalkine diminished endothelial function beyond the impairment already observed in CHF and was associated with a reduced responsiveness to the platelet inhibitor clopidogrel. These findings may indicate a novel pathophysiological mechanism contributing to impaired clopidogrel responsiveness in CHF.

High efficiency of antiviral CD4(+) killer T cells.

The destruction of infected cells by cytotxic T lymphocytes (CTL) is integral to the effective control of viral and bacterial diseases, and CTL function at large has long been regarded as a distinctive property of the CD8(+)T cell subset. In contrast, and despite their first description more than three decades ago, the precise contribution of cytotoxic CD4(+)T cells to the resolution of infectious diseases has remained a matter of debate. In particular, the CTL activity of pathogen-specific CD4(+) "helper" T cells constitutes a single trait among a diverse array of other T cell functionalities, and overall appears considerably weaker than the cytolytic capacity of CD8(+) effector T cells. Here, using an in vivo CTL assay, we report that cytotoxic CD4(+)T cells are readily generated against both viral and bacterial pathogens, and that the efficiency of MHC-II-restricted CD4(+)T cell killing adjusted for effector:target cell ratios, precise specificities and functional avidities is comparable in magnitude to that of CD8(+)T cells. In fact, the only difference between specific CD4(+) and CD8(+)T cells pertains to the slightly delayed killing kinetics of the former demonstrating that potent CTL function is a cardinal property of both antiviral CD8(+) and CD4(+)T cells.

Determinants of lipid goal achievement in patients on extended-release nicotinic acid/laropiprant in primary care clinical practice.

OBJECTIVES: To establish determinants of lipid goal attainment in primary care patients, with particular focus on participation in a disease management programme (DMP) on diabetes mellitus (DM) and/or coronary heart disease (CHD), with real-world practical relevance. METHODS: The present analysis was based on an observational study in 2359 patients with dyslipidaemia or hypercholesterolaemia that were treated with nicotinic acid 1000 mg/laropiprant 20 mg (Tredaptive) one or two tablets daily. Subgroups were formed by DMP participation (DMP vs. no DMP). A stepwise logistic regression model with backward selection of variables was applied to investigate factors influencing the probability of reaching lipid goals. Follow-up was 23 ± 7 weeks. RESULTS: Low density lipoprotein cholesterol (LDL-C) <100 mg/dl was achieved by 30.8% in DMP versus 26.8% (no DMP), high density lipoprotein (HDL-C) >40/50 mg/dl in 61.3% versus 66.1%, and triglycerides (TG) <150 mg/dl in 28.9% versus 31.7%. On multivariate analysis, age, sex, concomitant high-risk cardiovascular disease, or participation in a DMP appeared to have inconsistent effects on reaching LDL-C, HDL-C and TG goals. Likelihood to reach the LDL-C goal tended to be higher in males, in patients outside DMP, and in patients with DM or CHD, and those treated with 1 tablet (versus 2 tablets) extended release nicotinic acid 1000 mg/laropiprant 20 mg. The likelihood of reaching the HDL-C goal was higher in males and in patients without DM or DM+CHD (no effect of DMP). The likelihood of reaching the TG goals was higher in females, in patients outside DMP, and in patients with DM and/or CHD. Limitations include potential bias due to study design, physician and patient selection, and missing values at follow-up. CONCLUSION: DMP participation was not associated with overall improved lipid goal attainment. Physicians cannot predict the magnitude of effects of newly initiated lipid modifying therapy based on baseline characteristics of their patients.

Clinical Trial Educator program - a novel approach to accelerate enrollment in a phase III International Acute Coronary Syndrome Trial.

BACKGROUND: The conduct of current cardiovascular outcome trials requires investigation of thousands of patients at hundreds of investigator sites. Such large trials are clinically and logistically highly demanding and often tend to finish with significant delays, consequently delaying patient access to new medicines. PURPOSE: To address this issue, we designed and implemented a novel approach - a Clinical Trial Educator (CTE) program - to accelerate enrollment in the Thrombin-Receptor Antagonist for Clinical Event Reduction (TRA•CER) trial. This article analyzes the effect of this approach on the study milestones: patient recruitment, site start-up time, and recruitment rate. METHODS: Scientifically qualified and specifically trained CTEs regularly visited TRA•CER investigator sites in 18 European countries where they trained and educated investigators and site personnel to support them address recruitment challenges. Patient recruitment was assessed in absolute numbers and as recruitment rates, both in relation to CTE site visits. RESULTS: CTEs performed 2184 visits at 373 European TRA•CER sites (out of 921 global sites). Of sites visited by a CTE, significantly less remained without enrolling any patient than of sites not visited by a CTE (5.9% vs. 15.3%; p < 0.001). Sites visited within 30 days after initiation showed a significantly shortened median time to recruitment of the first patient (28 vs. 59 days with visits ≤30 or >30 days after initiation; p < 0.001). Mean patient recruitment rates were significantly higher at visited than at not-visited sites (1.13 vs. 0.89 patients per site per month, p < 0.001) and significantly increased after the first CTE site visit (from 0.70 to 1.17 patients per site per month; p < 0.001). Finally, there were fewer low-recruiting sites and more high-recruiting sites among the CTE-visited sites compared to the not-visited sites, and the mean recruitment rate at high-recruiting sites visited by CTEs was significantly higher than at high-recruiting sites without CTE visits (2.07 vs. 1.64 patients per site per month; p < 0.01). LIMITATIONS: The possibility for selection bias is inherent to this post hoc analysis of a nonrandomized data set. The European focus of the CTE program described here might add some geographical bias. Also, other activities such as investigator meetings conducted in parallel with CTE activities might have partly masked the results of our analysis. Finally, the analysis is limited to recruitment-related parameters, and the aspect of cost-effectiveness has not been quantitatively assessed. CONCLUSION: We found a significant positive association between CTE site visits and the assessed recruitment-related study milestones in the TRA•CER trial, and enrollment finished ahead of plan. We propose that a CTE program could efficiently accelerate enrollment in other clinical trials and therapeutic areas and could contribute to shortening patient access time to novel and potential lifesaving treatments in cardiovascular medicine and beyond.

Expression and regulation of chemokines in murine and human type 1 diabetes.

More than one-half of the ~50 human chemokines have been associated with or implicated in the pathogenesis of type 1 diabetes, yet their actual expression patterns in the islet environment of type 1 diabetic patients remain, at present, poorly defined. Here, we have integrated a human islet culture system, murine models of virus-induced and spontaneous type 1 diabetes, and the histopathological examination of pancreata from diabetic organ donors with the goal of providing a foundation for the informed selection of potential therapeutic targets within the chemokine/receptor family. Chemokine (C-C motif) ligand (CCL) 5 (CCL5), CCL8, CCL22, chemokine (C-X-C motif) ligand (CXCL) 9 (CXCL9), CXCL10, and chemokine (C-X3-C motif) ligand (CX3CL) 1 (CX3CL1) were the major chemokines transcribed (in an inducible nitric oxide synthase-dependent but not nuclear factor-κB-dependent fashion) and translated by human islet cells in response to in vitro inflammatory stimuli. CXCL10 was identified as the dominant chemokine expressed in vivo in the islet environment of prediabetic animals and type 1 diabetic patients, whereas CCL5, CCL8, CXCL9, and CX3CL1 proteins were present at lower levels in the islets of both species. Of importance, additional expression of the same chemokines in human acinar tissues emphasizes an underappreciated involvement of the exocrine pancreas in the natural course of type 1 diabetes that will require consideration for additional type 1 diabetes pathogenesis and immune intervention studies.

Sustained effects in hypercholesterolaemic patients on combined simvastatin/ezetimibe treatment: observational cohort study in clinical practice.

BACKGROUND: In order to reduce individual cardiovascular risk, many patients require life-long lipid-lowering therapy, often as a drug combination approach. We aimed to describe the usage pattern, effectiveness and tolerability of long-term treatment with lipid-lowering agents, with particular focus on an oral combination of simvastatin (SIM 10, 20, 40 or 80 mg) plus ezetimibe (EZ 10 mg). METHODS: A prospective, observational study in 512 general practices throughout Germany. From a sample of patients at moderate or high cardiovascular risk who had previously taken part in a half-year study of an SIM/EZ combination, 5485 patients were documented after 1 year of treatment (mean 58 +/- 16 weeks) with regard to lipid parameters, adverse drug reactions (ADRs) and adverse events. RESULTS: At the start of follow-up, 78.6% of patients were still on the SIM/EZ combination. At the end of follow-up, mean low density lipoprotein cholesterol (LDL-C) in patients on the combination versus those on other lipid-lowering therapy was reduced by 29.3 vs. 17.6% compared with baseline, total cholesterol by 23.1 vs. 14.5%, mean high density lipoprotein cholesterol (HDL-C) was increased by 15.9 vs. 13.4%, and mean triglycerides were reduced by 16.1 vs. 7.9%. Individual LDL-C targets were achieved by 56.6% on the SIM/EZ combination versus 35.9% on other therapy. In the long term (but not the short term), low acceptance of nutrition counselling as rated by the physician was associated with poor lipid levels. ADRs during follow-up occurred in 18 patients (0.3%; all cases non-serious), with seven cases of myalgia, and three cases each of nausea or arthralgia. CONCLUSIONS: This observational study showed that long-term therapy with the SIM/EZ combination resulted in sustained beneficial effects on serum lipids and was well-tolerated. Compared to patients with therapy discontinuations or switches, those remaining on the combination had better outcomes regarding lipid status.

Dual cholesterol inhibition with ezetimibe/simvastatin in pre-treated hypercholesterolaemic patients with coronary heart disease or diabetes mellitus: prospective observational cohort studies in clinical practice.

OBJECTIVE: Patients with primary hypercholesterolaemia and concomitant coronary heart disease (CHD) and/or diabetes mellitus (DM), who are at particularly high risk of cardiovascular events such as stroke or myocardial infarction, benefit from aggressive lipid lowering strategies. The present studies investigated the incremental efficacy and safety of dual cholesterol inhibition with ezetimibe/simvastatin in such high-risk patients pre-treated with statins but not reaching the 100 mg/dL (2.6 mmol/L) low density cholesterol (LDL-C) cholesterol threshold in the primary care setting. METHODS: Two open-label, prospective, non-randomised, observational studies (study 1 with n = 19 194 patients, predominantly with CHD; study 2 with n = 19 484 patients, predominantly with DM). Patients received--almost all after statin pre-treatment--ezetimibe 10 mg plus simvastatin 10 mg (study 1: 15%, study 2: 16%), 20 mg (in 68% each), 40 mg (12%/10%) or 80 mg (1%/1%) as fixed dose combinations over 3 months (dosage at investigator's discretion). RESULTS: Mean LDL-C was reduced by 28%/27% (study 1/ study 2) compared with baseline values (on statin monotherapy). Mean total cholesterol was decreased by 22% in each study, mean triglycerides by 16/17%, and mean high density cholesterol (HDL-C) was increased by 9/10%. Adverse events were reported in 0.3% and 0.2% of patients, respectively. CONCLUSION: Dual cholesterol inhibition with ezetimibe/simvastatin was effective and well tolerated under real practice conditions in high-risk patients with CHD and/or DM.

Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction.

OBJECTIVES: To investigate the effects of adding the selective aldosterone receptor antagonist eplerenone to ACE inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF). BACKGROUND: Addition of the non-selective aldosterone antagonist spironolactone to ACE-inhibitors reduces mortality and morbidity in CHF and improves endothelial vasomotor dysfunction, but is associated with considerable side-effects. METHODS: Starting 10 days after extensive myocardial infarction (MI) or sham-operation, Wistar rats were treated either with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), the selective aldosterone receptor antagonist eplerenone (EPL, 100 mg/kg per day) or a combination of both for 9 weeks. RESULTS: Maximum acetylcholine-induced, nitric oxide-dependent relaxation was significantly attenuated in aortic rings from rats with CHF compared with sham-operated animals (R(max) 55% vs. 87%). EPL alone slightly and TR significantly improved NO-mediated relaxation (CHF-EPL 66%; CHF-TR: 78%), while treatment with both EPL and TR completely restored endothelium-dependent vasorelaxation (CHF-EPL-TR: 83%). Aortic superoxide formation was significantly increased in rats with CHF compared with sham-operated animals, but was normalised by treatment with EPL or TR-EPL. Expression of the endothelial nitric oxide synthase was decreased in CHF and normalised in all treatment groups. CONCLUSIONS: In experimental CHF, the selective aldosterone antagonist EPL reduced the increased vascular superoxide formation. Although a combination of TR and EPL normalised endothelium-dependent relaxation, ACE inhibition as a monotherapy was almost equally effective.

Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction: role of vascular superoxide anion formation and endothelial nitric oxide synthase expression.

OBJECTIVES: We sought to investigate the effects of adding spironolactone (SP) to angiotensin-converting enzyme (ACE) inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF). BACKGROUND: Adding SP to ACE inhibitors reduces mortality and morbidity in CHF. Endothelial vasomotor dysfunction contributes to increased peripheral vascular resistance and reduced myocardial perfusion in CHF. METHODS: Seven days after extensive myocardial infarction (CHF) or sham operation, Wistar rats were treated with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), SP (10 mg/kg per day) or a combination of both for 11 weeks. RESULTS: Maximal acetylcholine-induced, nitric oxide (NO)-dependent relaxation was significantly attenuated in aortic rings from rats with CHF as compared with sham-operated animals (R(max) 44 +/- 3% vs. 63 +/- 3%). Spironolactone alone had no influence (46 +/- 5%) and TR improved NO-mediated relaxation (55 +/- 4%), whereas treatment with both completely restored endothelium-dependent vasorelaxation (64 +/- 4%). Aortic superoxide formation was significantly increased in rats with CHF as compared with sham-operated animals, but was normalized by treatment with SP or SP plus TR. In addition, aortic messenger ribonucleic acid expression of the oxidase subunit p22(phox) in rats with CHF was significantly reduced by SP or TR plus SP. Endothelial NO synthase expression was increased in TR-treated animals. Incubation of isolated porcine coronary arteries with SP dose-dependently attenuated superoxide formation. CONCLUSIONS: Spironolactone added to an ACE inhibitor normalizes NO-mediated relaxation in experimental CHF by beneficially modulating the balance of NO and superoxide anion formation.