Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes

OBJECTIVE: Mortality in type 1 diabetic patients with end-stage renal failure is high and dominated by coronary atherosclerotic events. With regard to prognosis, simultaneous transplantation of pancreas and kidney (SPK) may be superior to kidney transplantation alone (KTA) in type 1 diabetic patients, because normalization of blood glucose levels may reduce progression of coronary atherosclerosis and because it is well known that progression of coronary atherosclerosis is one of the major factors that determines clinical prognosis. However, no data are available on progression of coronary atherosclerosis after SPK. RESEARCH DESIGN AND METHODS: We performed an observational angiographic study comparing progression of coronary atherosclerosis, analyzed with quantitative coronary angiography, in patients with (n = 26) and those without (n = 6) a functioning pancreas graft after SPK, to test the hypothesis that normalization of blood glucose levels by SPK may indeed reduce progression of coronary atherosclerosis in type 1 diabetic patients and thereby improve prognosis. RESULTS: Mean follow-up was 3.9 years. Average glucose control was significantly worse for the patients without a pancreas graft than for patients with a functioning pancreas graft: 11.3 (SD 3.5) vs. 5.9 mmol/l (SD 1.1) (P = 0.03). Mean segment diameter loss (progression of diffuse coronary atherosclerosis) was 0.024 mm/year (SD 0.067) in patients with a functioning pancreas graft, compared with 0.044 mm/year (SD 0.038) in patients in whom the pancreas graft was lost. Minimum obstruction diameter loss (progression of focal coronary atherosclerosis) was 0.037 mm/year (SD 0.086) in patients with a functioning pancreas graft compared with 0.061 mm/year (SD 0.038) in patients in whom the pancreas graft was lost. Regression of atherosclerosis occurred in 38% of patients with a functioning pancreas graft compared with 0% of patients of whom the pancreas graft was lost (P = 0.035). CONCLUSIONS: Our study provides, for the first time, evidence that in patients who have undergone SPK, progression of coronary atherosclerosis in patients with a functioning pancreas graft is reduced compared with patients with pancreas graft failure. Our observation is an important part of the explanation for the observed improved mortality rates reported in type 1 diabetic patients with end-stage renal failure after SPK compared with KTA. In light of these findings described above, SPK must to be carefully considered for all diabetic transplant candidates.     

Apolipoprotein concentrations during treatment and recurrent coronary artery disease events

The effect of untreated total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) as cardiovascular risk factors in both primary and secondary prevention has been extensively investigated. The predictive value of on-treatment lipid and apolipoprotein levels on subsequent cardiovascular events is as yet uncertain. Eight hundred forty-eight patients (675 men and 173 women) with angiographically proven coronary artery disease (CAD) who received effective statin therapy (>/=30% decrease of baseline TC) were studied. We analyzed the predictive value of on-treatment levels of TC, LDL-C, triglycerides (TG), apolipoprotein A-I (apoA-I) and apolipoprotein B (apoB) on subsequent myocardial infarction (MI) and all cause mortality. On-treatment LDL-C levels were 2.55+/-0.55 mmol/L and 2.58+/-0.62 mmol/L for men and women respectively. Age-adjusted Cox regression analysis showed that only on-treatment apoA-I was predictive for future CAD events in both men and women, whereas on-treatment HDL-C was exclusively predictive in women. On-treatment apoB levels were predictive for recurrent CAD events in the total population but not after separate analysis for men and women. On-treatment levels of TC, LDL-C, and TG did not predict subsequent events. Multivariate analysis showed that on-treatment apoA-I and apoB were the only significant predictors for future cardiovascular events. On-treatment levels of TC, LDL-C, and TG were no longer associated with increased risk of recurrent cardiovascular events in CAD patients treated to target levels, which justifies the current guidelines. However, on-treatment levels of apoB and in particular apoA-I (and HDL-C in women) were significantly predictive for MI and all-cause mortality and may therefore be more suitable for cardiovascular risk assessment in this population.     

The influence of established genetic variation in the haemostatic system on clinical restenosis after percutaneous coronary interventions

Since activation of the haemostatic system is an important feature of the wound healing response triggered by arterial injury, variations in genes involved in thrombus formation may play a role in restenosis after percutaneous coronary interventions (PCI). Therefore, our aim was to examine the relationship between polymorphisms that are known to play a role in the haemostatic system and the risk of clinical restenosis in the GENetic DEterminants of Restenosis (GENDER) study, a multicenter prospective study design that enrolled 3,104 consecutive patients after successful PCI. Target vessel revascularization (TVR) was the primary endpoint. All patients were genotyped for six polymorphisms in the Factor II, Factor V, Factor VII and PAI-1 genes. The PAI-1 4G variant was associated with an increased risk of TVR. When compared to 5G/5G homozygotes, heterozygous patients were at higher risk for TVR (HR: 1.46, 95% CI: 1.05-2.03), whereas patients with the 4G/4G genotype had an even further increased risk (HR: 1.69, 95% CI: 1.19-2.41). In contrast, the factor V 506Gln (factor V Leiden) amino acid substitution was associated with a decreased risk of TVR (HR: 0.41, 95% CI: 0.19-0.86). Our findings indicate that polymorphisms in the factorV and PAI-1 genes may play a role in the process of restenosis.     

Multivariate random-effects approach: for meta-analysis of cancer staging studies

RATIONALE AND OBJECTIVES: Meta-analyses of diagnostic accuracy studies produce summary estimates of sensitivity and specificity. Cancer staging relies on staging systems and meta-analysis is often performed after dichotomization of the staging results. For each dichotomization, summary estimates of sensitivity and specificity can be calculated by repeated bivariate random-effects analyses. In this process, staging information is lost and under- and overstaging can not be adequately expressed. MATERIALS AND METHODS: We propose a new multivariate random-effects approach, which is an extension of the bivariate random-effects approach. To illustrate the principles and outcomes of both approaches, we used data from a meta-analysisevaluating endoluminal ultrasonography in staging of rectal cancer. In the multivariate approach, results on correct staging and under- and overstaging were calculated. In addition, the results from this analysis were used to calculate sensitivity and specificity estimates for each dichotomization and these estimates were compared with the results of the repeated bivariate analyses. RESULTS: By the multivariate analysis, results on correct staging and under- and overstaging were obtained. The sensitivity and specificity estimates for the dichotomizations, calculated from the results of this multivariate approach, were also comparable with the sensitivity and specificity estimates obtained by the repeated bivariate analyses. CONCLUSIONS: The multivariate random-effects approach can be a useful meta-analytic method for summarizing cancer staging data presented in diagnostic accuracy studies.     

Metabolic Background Determines the Importance of NOS3 Polymorphisms in Restenosis after Percutaneous Coronary Intervention: A Study in Patients with and without the Metabolic Syndrome

Variation in the NOS3 gene has been related to the development of restenosis. The Glu298Asp polymorphism has previously been investigated for its effect on NO levels and the development of restenosis. However, the variability of findings gave rise to the hypothesis that the functional significance of this polymorphism may only become manifest under conditions of endothelial dysfunction. Since patients with the metabolic syndrome are known to have endothelial dysfunction, we aimed to investigate if the significance of NOS3 polymorphisms may depend on the presence of the metabolic syndrome.We examined the impact of the -949 A/G, the -716 C/T and the Glu298Asp polymorphisms in the NOS3 gene on the risk of clinical restenosis in a previously described subpopulation of the GENDER-study, a multicenter prospective study design that enrolled consecutive patients after successful PCI. This subpopulation consisted of 901 patients of whom sufficient data were available to establish absence or presence of the metabolic syndrome. Of these patients, 448 had the metabolic syndrome. Clinical restenosis, defined as target vessel revascularization (TVR), was the primary endpoint.We demonstrated that the minor -949G, -716T and 298Asp alleles were associated with a significantly increased risk of TVR in patients with the metabolic syndrome (HR: 1.58 [95%CI: 1.04–2.40], HR: 1.95 [95%CI: 1.02–3.70] and HR: 1.67 [95%CI: 1.09–2.54], respectively). In the group without the metabolic syndrome we observed no association between the three polymorphisms and TVR.     

Clinical trials: odds ratios and multiple regression models--why and how to assess them

Odds ratios (ORs), unlike chi2 tests, provide direct insight into the strength of the relationship between treatment modalities and treatment effects. Multiple regression models can reduce the data spread due to certain patient characteristics and thus improve the precision of the treatment comparison. Despite these advantages, the use of these methods in clinical trials is relatively uncommon. Our objectives were (1) to emphasize the great potential of ORs and multiple regression models as a basis of modern methods; (2) to illustrate their ease of use; and (3) to familiarize nonmathematical readers with these important methods. Advantages of ORs are multiple. (1) They describe the probability that people with a certain treatment will have an event, versus those without the treatment, and are therefore a welcome alternative to the widely used chi2 tests for analyzing binary data in clinical trials. (2) statistical software of ORs is widely available. (3) Computations using risk ratios (RRs) are less sensitive than those using ORs. (4) ORs are the basis for modern methods such as meta-analyses, propensity scores, logistic regression, and Cox regression. For analysis, logarithms of the ORs have to be used; results are obtained by calculating antilogarithms. A limitation of the ORs is that they present relative benefits but not absolute benefits. ORs, despite a fairly complex mathematical background, are easy to use, even for nonmathematicians. Both linear and logistic regression models can be adequately applied for the purpose of improving precision of parameter estimates such as treatment effects. We caution that, although application of these models is very easy with computer programs widely available, the fit of the regression models should always be carefully checked, and the covariate selection should be carefully considered and sparse. We do hope that this article will stimulate clinical investigators to use ORs and multiple regression models more often.     

Clinical trials: how to assess confounding and why so

Background: In large randomized controlled trials the risk of random imbalance of the covariates is mostly negligible. However, with smaller studies it may be substantial. In the latter situation assessment and adjustment for confounders is a requirement in order to reduce a biased assessment of the treatment comparison. Objective: In the current paper three methods for confounding assessment and adjustment are reviewed for a nonmathematical readership. Methods: First method, subclassification: the study population is divided into subclasses with the same subclass characteristic, then, treatment efficacy is assessed per subclass, and, finally, a weighted average is calculated. Second method, regression modeling: in a multivariable regression model with treatment efficacy as independent and treatment modality as dependent variable, the covariates at risk of confounding are added as additional dependent variables to the model. An analysis adjusted for confounders is obtained by removing the covariates that are not statistically significant. Third method, propensity scores: each patient is assigned several odds ratios (ORs), which are his/her probability, based on his/her covariate value of receiving a particular treatment modality. A propensity score per patient is calculated by multiplying all of the statistically significant ORs. These propensity scores are, then, applied for confounding adjustment using either subclassification or regression analysis. Conclusions: The advantages of the first method include that empty subclasses in the treatment comparison are readily visualized, and that subclassification does not rely on a linear or any other regression model. A disadvantage is, that it can only be applied for a single confounder at a time. The advantage of the second method is, that multiple variables can be included in the model. However, the number of covariates is limited by the sample size of the trial. An advantage of the third method is, that it is generally more reliable and powerful with multiple covariates than regression modeling. However, irrelevant covariates and very large / small ORs reduce power and reliability of the assessment. The above methods can not be used for the assessment of interaction in the data.     

Use of fecal occult blood testing in hospitalized patients: Results of an audit

BACKGROUND:

The fecal occult blood test (FOBT), widely used as a colorectal cancer screening tool, continues to be used in hospitalized patients. However, the utility of this test for hospitalized patients is unclear.

OBJECTIVE:

To assess FOBT use in a large urban regional health authority.

METHODS:

Reports of all FOBTs performed between April 1, 2011 and March 30, 2012 from two academic and four community hospitals in Winnipeg (Manitoba) were extracted. Of 650 hospitalizations with a positive FOBT result and 1254 with a negative FOBT result, random samples of 230 and 97 charts, respectively, were reviewed. Information including demographics, admission diagnos(es), indication(s) for ordering the FOBT and clinical management was extracted.

RESULTS:

Thirty-four percent (650 of 1904) of hospitalizations with an FOBT had a positive FOBT result. Family medicine physicians ordered approximately one-half of the reviewed FOBTs. The most common indication for ordering an FOBT was anemia. Of those with a positive FOBT, 66% did not undergo further gastrointestinal investigations. Of those with a positive FOBT and overt gastrointestinal bleeding and/or melena who underwent endoscopy, 60% had their endoscopy performed before the FOBT result being reported while 38% underwent their endoscopy ≥3 days after the stool sample was collected. There were minimal differences in clinical practices between academic and community hospitals.

CONCLUSIONS:

The present study suggests that FOBT results in hospitalized patients may have little beneficial impact on clinical management. Hospital laboratories may be better served in directing resources to other tests.