Cost-effectiveness of case-based training for primary care physicians in evidence-based medicine of patients with coronary heart disease.

BACKGROUND: We have shown that a case-based training programme for general practitioners, aimed to implement evidence-based care of patients at very high risk of coronary death, was associated with decreased mortality. In the present study we assessed long-term cost-effectiveness of this programme. DESIGN: Registry-based long-term cost-effectiveness analysis on a clinical trial. METHODS: Costs of the programme, health care, drugs and added years of life were included. Costs were adjusted to 2012 level and discounted by 3%. Life-years gained were estimated as the difference between the survival curves of the trial. The effectiveness measure, quality adjusted life-years (QALYs), was constructed by multiplying each life-year with a quality of life weight corresponding to the health status of that year. QALYs were also discounted by 3%. Incremental cost-effectiveness ratio (ICER) was estimated as the incremental cost per QALY gained. RESULTS: The number of undiscounted life-years gained was 365 days in the intervention group as compared to control (p = 0.02). The number of discounted QALYs gained was 0.66. The net increase in total costs was estimated as 17,862 € when costs of added years of life were included and 4621 € exclusive of these costs. This implied an ICER of 27,063 € per gained QALY. This ICER is well below commonly used threshold values of the societal willingness to pay for a QALY. CONCLUSIONS: The results show that a case-based training programme of general practitioners is a cost-effective way to save years of life in patients with very high risk of coronary death.

Antecedents and characteristics of lean thinking implementation in a Swedish hospital: a case study.

Despite the reported success of Lean in health care settings, it is unclear why and how organizations adopt Lean and how Lean transforms work design and, in turn, affects employees' work. This study investigated a cardiology department's journey to adopt and adapt Lean. The investigation was focused on the rationale and evolution of the Lean adoption to illuminate how a department with a long quality improvement history arrived at the decision to introduce Lean, and how Lean influenced employees' daily work. This is an explanatory single case study based on semistructured interviews, nonparticipant observations, and document studies. Guided by a Lean model, we undertook manifest content analysis of the data. We found that previous improvement efforts may facilitate the introduction of Lean but may be less important when forecasting whether Lean will be sustained over time. Contextual factors seemed to influence both what Lean tools were implemented and how well the changes were sustained. For example, adoption of Lean varied with the degree to which staff saw a need for change. Work redesign and teamwork were found helpful to improve patient care whereas problem solving was found helpful in keeping the staff engaged and sustaining the results over time.

Identification and predictive value of interleukin-6+ interleukin-10+ and interleukin-6- interleukin-10+ cytokine patterns in ST-elevation acute myocardial infarction.

RATIONALE: At the onset of ST-elevation acute myocardial infarction (STEMI), patients can present with very high circulating interleukin-6 (IL-6(+)) levels or very low-IL-6(-) levels. OBJECTIVE: We compared these 2 groups of patients to understand whether it is possible to define specific STEMI phenotypes associated with outcome based on the cytokine response. METHODS AND RESULTS: We compared 109 patients with STEMI in the top IL-6 level (median, 15.6 pg/mL; IL-6(+) STEMI) with 96 in the bottom IL-6 level (median, 1.7 pg/mL; IL-6(-) STEMI) and 103 matched controls extracted from the multiethnic First Acute Myocardial Infarction study. We found minimal clinical differences between IL-6(+) STEMI and IL-6(-) STEMI. We assessed the inflammatory profiles of the 2 STEMI groups and the controls by measuring 18 cytokines in blood samples. We exploited clustering analysis algorithms to infer the functional modules of interacting cytokines. IL-6(+) STEMI patients were characterized by the activation of 2 modules of interacting signals comprising IL-10, IL-8, macrophage inflammatory protein-1α, and C-reactive protein, and monocyte chemoattractant protein-1, macrophage inflammatory protein-1ß, and monokine induced by interferon-γ. IL-10 was increased both in IL-6(+) STEMI and IL-6(-) STEMI patients compared with controls. IL-6(+)IL-10(+) STEMI patients had an increased risk of systolic dysfunction at discharge and an increased risk of death at 6 months in comparison with IL-6(-)IL-10(+) STEMI patients. We combined IL-10 and monokine induced by interferon-γ (derived from the 2 identified cytokine modules) with IL-6 in a formula yielding a risk index that outperformed any single cytokine in the prediction of systolic dysfunction and death. CONCLUSIONS: We have identified a characteristic circulating inflammatory cytokine pattern in STEMI patients, which is not related to the extent of myocardial damage. The simultaneous elevation of IL-6 and IL-10 levels distinguishes STEMI patients with worse clinical outcomes from other STEMI patients. These observations could have potential implications for risk-oriented patient stratification and immune-modulating therapies.

Genetic and environmental influences on the plasma interleukin-6 concentration in patients with a recent myocardial infarction: a case-control study.

The aim was to study the stimuli responsible for triggering and sustaining the plasma concentration of the inflammatory marker interleukin-6 (IL-6) in patients with a first myocardial infarction before the age of 60 and healthy control subjects matched for age and sex. The plasma IL-6 concentration, antibodies against Chlamydia pneumoniae, cytomegalovirus, Epstein-Barr virus, Helicobacter pylori, herpes simplex type 1 and 2, and genotype for the IL6-174 G>C single-nucleotide polymorphism were determined 3 months after the acute event. The results showed that patients had higher IL-6 levels than control subjects, whereas there were no differences regarding individual or total number (pathogen burden) of positive antibody tests against the different pathogens or IL6 genotype distribution. The plasma IL-6 concentration was associated with the number of positive antibody tests in patients and control subjects, whereas patients irrespective of IL6 genotype had increased IL-6. Multivariate analysis, including traditional coronary heart disease risk factors, antibodies against pathogens, and IL6 genotype, explained 17% of the variation of the plasma IL-6 concentration. Neither pathogen burden nor IL6 genotype did contribute to the variation of plasma IL-6 levels, whereas smoking, body-mass index, hypertension, case-control status, and age were determinants of the plasma IL-6 concentration.

Coagulation factor VII and inflammatory markers in patients with coronary heart disease.

To further elucidate the connection between inflammation and factor VII (FVII) taking genetic variation in the FVII locus into account, we have examined 387 patients after myocardial infarction and 387 age-matched and sex-matched healthy control individuals. Circulating levels of C-reactive protein, FVII antigen (FVIIag), activated FVII (FVIIa), fibrinogen and interleukin-6 were analysed and all subjects were genotyped for the Arg353Gln polymorphism in the FVII locus. Plasma concentrations of C-reactive protein, fibrinogen, and interleukin-6 were higher among patients than control individuals. FVIIag was lower in the patient group, but for FVIIa there was no difference between the two groups. Among the inflammatory markers, only C-reactive protein indicated a weak nonlinear association with FVII. No significant difference in frequency of the Gln allele was observed between patients and control individuals but the presence of the Gln allele was associated with lower plasma levels of FVIIag and FVIIa in both groups. The low-grade chronic inflammation seen 3 months after myocardial infarction is not of major importance for the variation in plasma concentration of FVII. The presence of the Gln allele in the Arg353Gln polymorphism in the FVII locus did not differ between patients and control individuals but was associated with lower plasma levels of FVIIag and FVIIa that could have a protective effect against myocardial infarction. To further elucidate these facts, a prospective study should be performed to reduce the risk of a possible selection bias due to coronary heart disease death seen in retrospective case-control studies.

A high-fat meal is accompanied by increased plasma interleukin-6 concentrations.

BACKGROUND AND AIM: Enhanced and prolonged postprandial lipaemia is associated with coronary heart disease (CHD). However, the mechanisms linking postprandial lipaemia to the increased risk of atherosclerosis and CHD remain to be determined. The aim of the present study was to examine the effects of a high-fat meal on plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and cellular adhesion molecules in CHD patients and control subjects. METHODS AND RESULTS: Forty-one middle-aged men with premature CHD and 26 healthy male controls were investigated. The plasma triglyceride response to the high-fat meal was significantly greater among cases than controls. The oral fat load induced a twofold increase in plasma concentrations of IL-6, an increase that was similar in CHD patients and control subjects. No changes could be detected in plasma concentrations of cellular adhesion molecules in response to postprandial lipaemia in either CHD patients or control subjects. CONCLUSION: The results of the present study suggest that a high-fat meal affects mechanisms that induce increased inflammatory activity, which is recognised as a key modulator in the development of atherosclerosis and CHD. However, the increased levels of plasma IL-6 appear not to be determined by the magnitude of the postprandial triglyceridaemia.

Genotype-specific increase in plasma concentrations of activated coagulation factor VII in response to experimental inflammation. A link between infection and acute myocardial infarction?

There is evidence that infection and inflammation might trigger an acute coronary event, but the mechanisms are unclear. Activated factor VII (FVIIa) is a potent coagulant that is under genetic control and a potential determinant of the outcome of acute myocardial infarction. This study investigated the acute FVIIa response to experimental inflammation. Forty healthy men and women were vaccinated with 1 ml of Salmonella Typhii vaccine. Plasma levels of FVIIa, FVII antigen (FVIIag), tissue factor (TF) activity and thrombin-antithrombin complex (TAT) were measured at baseline and up to 24 hours after inoculation. All subjects were genotyped for the FVII gene Arg353Gln polymorphism. Plasma concentrations of FVIIa, but not FVIIag, increased significantly with a peak at 10 hrs after vaccination. At 24 hrs FVIIa levels had returned to baseline. The FVIIa response to vaccination was significantly greater in subjects with the ArgArg genotype compared with ArgGln subjects. TAT increased, but TF activity was unchanged after vaccination. The results are of interest from a mechanistic viewpoint, since one explanation for the link between infection and acute myocardial infarction might be activation of coagulation. However, there is a need for further studies of the role of infection and inflammation in haemostasis.

Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases?

BACKGROUND: A single-nucleotide polymorphism (SNP) in the promoter region of the interleukin-6 (IL-6) gene at position -174 (G>C) has been reported to be associated with a variety of major diseases, such as Alzheimer disease, atherosclerosis, and cardiovascular disease, cancer, non-insulin-dependent diabetes mellitus, osteoporosis, sepsis, and systemic-onset juvenile chronic arthritis. However, authors of previous in vitro and in vivo studies have reported conflicting results regarding the functionality of this polymorphism. We therefore aimed to clarify the role of the -174 SNP for the induction of IL-6 in vivo. METHODS: We vaccinated 20 and 18 healthy individuals homozygous for the -174 C and G alleles, respectively, with 1 mL of Salmonella typhii vaccine. IL-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured in the blood at baseline and up to 24 h after vaccination. RESULTS: Individuals with the G genotype had significantly higher plasma IL-6 values at 6, 8, and 10 h after vaccination than did individuals with the C genotype (P <0.005). There were no differences between the two genotypes regarding serum concentrations of IL-1beta and TNF-alpha before or after vaccination. CONCLUSIONS: The -174 G>C SNP in the promoter region of the IL-6 gene is functional in vivo with an increased inflammatory response associated with the G allele. Considering the central role of IL-6 in a variety of major diseases, the present finding might be of major relevance.

Prognostic value of plasma interleukin-6 concentrations and the -174 G > C and -572 G > C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis.

The present study was performed to investigate the prognostic value of plasma interleukin-6 (IL-6) concentrations and promoter polymorphisms of the IL-6 gene in patients with acute myocardial infarction treated with thrombolysis. Two hundred and eight patients with myocardial infarction treated with thrombolysis were included and followed for 2-5 years. Plasma concentrations of IL-6 were measured at admission and 48 h after admission. Genotyping for the -174 G > C and -572 G > C IL-6 polymorphisms was performed. Patients who died of cardiovascular causes or suffered a new myocardial infarction during follow-up had increased plasma concentrations of IL-6 at admission (P < 0.002) and at 48 h after admission (P < 0.05) compared with patients who had an uneventful course. IL-6 levels above the median at admission were independently associated with a worse prognosis. No associations were found between IL-6 levels and the promoter polymorphisms. The -174 G > C polymorphism was not associated with cardiovascular death or a new myocardial infarction, whereas the -572 G > C polymorphism showed a borderline significant increase in risk (P = 0.05) in univariate analysis. In conclusion, the early IL-6 response during myocardial infarction is associated with prognosis in patients with Q-wave myocardial infarction, whereas no associations were found between IL-6 genotype and phenotype.