Controversies in the Use of Beta Blockers in Heart Failure

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94510/1/j.1527-5299.2003.00294.x.pd

Niacin or Ezetimibe for Patients with, or at Risk of Coronary Heart Disease

Coronary heart disease treatment with HMG-CoA reductase inhibitors has been very successful. There is increasing interest in adding other lipid lowering therapy, primarily as additional therapy onto HMG-CoA reductase therapy. This paper will examine two of the more popular secondary agents, ezetimibe and niacin, and describe their research data and potential for usefulness in further reducing cardiovascular events

Neutrophil to lymphocyte ratio is not related to carotid atherosclerosis progression and cardiovascular events in the primary prevention of cardiovascular disease: results from the IMPROVE study

Inflammation is a component of the pathogenesis of atherosclerosis and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). The neutrophil to lymphocyte ratio (NLR) is a possible inflammation metric for the detection of ASCVD risk, although results of prospective studies are highly inconsistent on this topic. We investigated the cross‐sectional relationship between NLR and carotid intima‐media thickness (cIMT) in subjects at moderate‐to‐high ASCVD risk. The prospective association between NLR, cIMT progression, and incident vascular events (VEs) was also explored. In 3341 subjects from the IMT‐Progression as Predictors of VEs (IMPROVE) study, we analyzed the association between NLR, cIMT, and its 15‐month progression. The association between NLR and incident VEs was also investigated. NLR was positively associated with cross‐sectional measures of cIMT, but not with cIMT progression. The association between NLR and cross‐sectional cIMT measures was abolished when adjusted for confounders. No association was found between NRL and incident VEs. Similarly, there were no significant differences in the hazard ratios (HRs) of VEs across NLR quartiles. NLR was neither associated with the presence and progression of carotid atherosclerosis, nor with the risk of VEs. Our findings do not support the role of NLR as a predictor of the risk of atherosclerosis progression and ASCVD events in subjects at moderate‐to‐high ASCVD risk, in primary prevention. However, the usefulness of NLR for patients at a different level of ASCVD risk cannot be inferred from this study

Determinants of carotid wall echolucency in a cohort of European high cardiovascular risk subjects: A cross-sectional analysis of IMPROVE baseline data

Echolucency, a measure of plaque instability associated with increased cardiovascular risk, can be assessed in both the carotid plaque and the plaque-free common carotid intima–media (IM) complex as a gray-scale median (plaque-GSM and IM-GSM, respectively). The impact of specific vascular risk factors on these two phenotypes remains uncertain, including the nature and extent of their influence. This study aims to seek the determinants of plaque-GSM and IM-GSM. Plaque-GSM and IM-GSM were measured in subjects from the IMPROVE study cohort (aged 54–79, 46% men) recruited in five European countries. Plaque-GSM was measured in subjects who had at least one IMTmax ≥ 1.5 mm (n = 2138), whereas IM-GSM was measured in all subjects included in the study (n = 3188). Multiple regression with internal cross-validation was used to find independent predictors of plaque-GSM and IM-GSM. Plaque-GSM determinants were plaque-size (IMTmax), and diastolic blood pressure. IM-GSM determinants were the thickness of plaque-free common carotid intima–media complex (PF CC-IMTmean), height, systolic blood pressure, waist/hip ratio, treatment with fibrates, mean corpuscular volume, treatment with alpha-2 inhibitors (sartans), educational level, and creatinine. Latitude, and pack-yearscode were determinants of both plaque-GSM and IM-GSM. The overall models explain 12.0% of plaque-GSM variability and 19.7% of IM-GSM variability. A significant correlation (r = 0.51) was found between plaque-GSM and IM-GSM. Our results indicate that IM-GSM is a weighty risk marker alternative to plaque-GSM, offering the advantage of being readily measurable in all subjects, including those in the early phases of atherosclerosis where plaque occurrence is relatively infrequent

Carotid intima media thickness (IMT) and IMT-progression as predictors of vascular events in a high risk european population

The intima-media thickness (IMT) of extracranial carotid arteries, assessed by ultrasound techniques, has been shown to be associated with most vascular risk factors for atherosclerosis and with the prevalence and extent of cardiovascular disease and coronary atherosclerosis. On this basis, this ultrasonic variable has been proposed as a surrogate index of atherosclerosis of other vascular regions. Studies have supported this hypothesis showing that IMT is a good predictor of new myocardial infarction and stroke. However, limited information has been provided on the relationship between IMT-progression, that is the real end point used in pharmacological studies, and cardiovascular events. Generally, attempts to delay IMT-progression using "anti-atherosclerotic" agents have provided encouraging results. However, no one of the studies so far published has been able to address, on a prospective basis, whether IMT-progression may effectively reflect the efficacy of the treatment in reducing the rate of cardiovascular events. To address these issues we designed \u201cthe IMPROVE study\u201d, a currently on going prospective multicenter, longitudinal, long-term, observational study funded by the European community. The major objective of the IMPROVE study is to evaluate the association between IMT, IMT-progression and the rate of new vascular events in subjects at high risk of atherosclerosis. The effect of gene polymorphisms, lipid peroxidation, socio-economic and psychological variables on the same ultrasonic end points will be also evaluated. In order to achieve the project objectives, 3600 patients will be recruited in 7 European countries and followed ultrasonically and clinically for 30 months. Clinical events will be monitored up to 36 months. Data will be analysed with conventional statistics and with innovative approaches based on artificial neural networks. The study is considered as positive if a difference of at least 3% in the cumulative incidence of acute vascular events between the lowest and the highest quintiles of IMT or IMT-progression is detected. A summary of aims and design of the study will be presented

Issue with models of integration : "The IMPROVE Study"

Epidemiological and clinical evidence indicates that < 50% of cardiovascular events are explained by vascular risk factors (VRFs), thus justifying for the need of alternative or integrated biomarkers to better stratify the patient risk. The intima-media thickness (IMT) of extracranial carotid arteries, measured by high-resolution B-mode ultrasound, is widely used to investigate the effects of conventional and non-conventional VRFs as well as the association with end-organ damage. In view of its correlation with coronary atherosclerosis, IMT has been proposed as an useful surrogate marker of atherosclerosis in carotid arteries and in other vascular regions. IMT is a good predictor of new myocardial infarction and it has been shown to be influenced by drugs known to reduce cardiovascular events, which supports the concept that IMT represents a biomarker of atherosclerosis. Carotid IMT alone has the same predictive capacity of VRFs. In a longitudinal - observational study, we have shown that the integrated use of VRFs included into the Framingham risk score and ultrasonic measurements of carotid IMT significantly increase their capacity to predict cardiovascular events in patients at low/intermediate risk. The integration of carotid IMT with non conventional VRFs (gene polymorphisms, oxidative burden, psyco or socioeconomic aspects etc.) may further optimize the stratification of patient risk. Another important carotid ultrasonic variable that may have predictive capacity, alone or when integrated with conventional or non conventional risk factors, is the progression of carotid IMT. A prospective, multicenter, longitudinal, long-term, observational study (The IMPROVE study) is currently ongoing. It aims to investigate the capacity of both cross sectional carotid IMT and overall IMT-progression to predict alone, or after integration with both conventional and non conventional VRF, the rate of new vascular events in an European population classified at high risk of cardiovascular disease for the presence of at least 3 VRFs. The patients\u2019 enrolment ended in April 2005 and a total of 3711 patients were recruited in 6 European countries (1095 in Italy, 504 in France and 2140 in northern Europe). Funding: Research describing correlations between carotid and coronary atherosclerosis is supported by the Italian Ministry of Health. The improve study is supported by European Union (IMPROVE: QLG1-CT-2002-00896) References: 1. Measurement of carotid artery intima-media thickness in dyslipidemic patients increases the power of traditional risk factors to predict cardiovascular events. Baldassarre D, Amato M, Pustina L, Castelnuovo S, sancito S; Gerosa L; Veglia F, Keidar S, Tremoli E, Sirtori CR. Atherosclerosis. 2006 May 6; [Epub ahead of print]. 2. Carotid intima media thickness (IMT) and IMT-progression as predictors of vascular events in a high risk european population: \u201cthe IMPROVE study\u201d. Tremoli E, Baldassarre D, on behalf of the \u201cIMPROVE Study Group\u201d. Atherosclerosis. 2006;7(3):42. 3. Baldassarre D, Amato M, Bondioli A, Sirtori CR, Tremoli E. Carotid artery intima-media thickness measured by ultrasonography in normal clinical practice correlates well with atherosclerosis risk factors. Stroke 2000;31:2426-2430. 4. Baldassarre D, Amato M, Pustina L, Tremoli E, Sirtori CR, Calabresi L, Franceschini G. Increased carotid artery intima-media thickness in subjects with primary hypoalphalipoproteinemia. Arterioscler Thromb Vasc Biol 2002;22:317-322

Common carotid artery diameter as a promising new candidate marker of cardiovascular risk in the IMPROVE study cohort

Aim: To explore whether inter-adventitial common carotid artery diameter (CCAD) detected by B-mode ultrasound may be considered a candidate marker of cardiovascular risk. Methods: The baseline data of the IMPROVE study cohort, including 1776 men and 1935 women representative of an European population at high risk of cardiovascular diseases, were analysed to explore whether CCAD is associated with the extent of carotid atherosclerosis, independently of traditional vascular risk factors and anthropometric variables. Results: After adjustment for possible confounders (height, centre, reader and sonographer), CCAD was positively associated with male gender, age, weight, body mass index, waist, hip, waist/hip ratio, systolic and diastolic blood pressure, pulse pressure, triglycerides, blood glucose, uric acid, cigarette packyears and family history of peripheral vascular disease (all p<0.0001). In contrast, years elapsed since smoking cessation, total-, HDL- and LDL-cholesterol were negatively related to CCAD (all p<0.0001). In the full model adjusted for all these confounders, CCAD was positively associated with carotid wall thickness (p<0.0001 for both IMTmean and IMTmax) and with the prevalence of carotid segments with plaques (p<0.04). Conclusion: Inter-adventitial CCAD is positively associated with carotid atherosclerosis and with most vascular risk factors. These results suggest that CCAD is a promising candidate marker of cardiovascular risk. Completion of the IMPROVE study will allow to assess prospectively the value of CCAD to predict new vascular events, independently to VRFs and carotid IMT. Funding: European Project, IMPROVE QLG1-CT-2002-0089

Common carotid artery diameter as a marker of cardiovascular risk: preliminary results of the improve study

Background: The \u201cIMPROVE study\u201d was designed to investigate whether cross-sectional carotid artery intima media thickness (IMT) and overall IMT progression are predictors of vascular events in European individuals at high cardiovascular risk. Aim: To investigate whether C-IMT could be combined with inter-adventitial common carotid artery diameter (ICCAD) to improve the predictability of vascular events. Methods: IMPROVE is a prospective, multicenter, longitudinal, observational study. 3711 subjects (median age 64.4 years; 48% men) with at least 3 vascular risk factors (VRFs) were recruited in 7 centers in Finland, France, Italy, the Netherlands and Sweden. Collected variables included clinical, biochemical, genetic, socio-economic, psychological, nutritional, and educational data, personal and family history of diseases, drug intake and physical activity. 3703 patients were monitored for a median (IQR) follow-up of 36.2 (35.8-37.4) months. 215 patients suffered a first vascular event with an incidence of 20/1000 person-years. Results: In Cox proportional-hazards regression, C-IMTs were associated with vascular risk (combined end point) even after adjustment for VRFs (Ptrend <0.005 for all). ICCAD was associated with the risk of events independently of VRFs and C-IMTmax (HRadj for 1 SD increase: 1.26, 95% CI: 1.08-1.48, p=0.004). Results for cardio and cerebro-vascular events were in line with those observed with the combined end point. By ROC curves analysis, ICCAD alone has about the same predictive capacity of the best predictor among C-IMT variables (IMTmean). When combined, IMTmean and ICCAD provided a better predictive capacity than conventional VRFs (c-statistic = 0.653 vs. 0.639). Figure 1: Association of IMTmean-max and ICCAD with the incidence vascular events. The combination of IMTmean, ICCAD and VRFs further improved the total predictive capacity (c-statistic 0.669). Conclusions: ICCAD and C-IMT are independent predictors of cardiovascular events in European high-risk patients and together they enhance the predictive capacity of VRFs

Carotid diameter improves the carotid IMT capacity to predict coronary events : data from the IMPROVE study

Objective: to investigate whether measurement of carotid artery intima media thickness (IMT) could be combined with inter-adventitial common carotid artery diameter (CCAD) to improve the predictability of cardiovascular events. Background: The \u201cIMPROVE study\u201d is a prospective, longitudinal study designed to investigate whether cross-sectional IMT and IMT progression are predictors of vascular events in European individuals at high risk of cardiovascular diseases. Methods and results: 3711 subjects (median age 64.4 years; 48% men) with at least three vascular risk factors (VRFs) were recruited in 7 centers in Europe. 3703 patients were monitored for a median of 36.2 months. 215 patients suffered a first cardiovascular event with an incidence of 19.9 per 1000 person-years. In Cox proportional-hazards regression, C-IMT measures were associated with the risk of the combined end point even after adjustment for VRFs (Ptrend <0.005 for all). CCAD was associated with the risk of events independently of VRFs and C-IMTmax (adjusted HR for 1 SD increase: 1.26, 95% CI: 1.08-1.48, p=0.004). Results for cardio and cerebro-vascular events were in line with those observed with the combined end point. By ROC curves analysis, CCAD alone has about the same predictive capacity of the best predictor among C-IMT variables (IMTmean). When combined, IMTmean and CCAD provided a better predictive capacity than conventional VRFs (c-statistic = 0.653 vs. 0.639). The combination of IMTmean, CCAD and VRFs further improved the total predictive capacity (c-statistic 0.669). Conclusions: CCAD and C-IMT are independent predictors of cardiovascular events and together they enhance the predictive capacity of VRFs