Evolution of renal function and predictive value of serial renal assessments among patients with acute coronary syndrome: BIOMArCS study.

BACKGROUND: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. METHODS: From 844 ACS patients included in the BIOMArCS study, we analysed patient-specific longitudinal marker trajectories from the case-cohort of 187 patients to determine the risk of the endpoint (cardiovascular death or hospitalization for recurrent non-fatal ACS) during 1-year follow-up. Study included only patients with eGFRCr ≥ 30 ml/min/1.73 m2. Survival analyses were adjusted for GRACE risk score and based on data >30 days after the index ACS (mean of 8 sample per patient). RESULTS: Mean age was 63 years, 79% were men, 43% had STEMI, and 67% were in eGFR stages 2-3. During hospitalization for index ACS (median [IQR] duration: 5 (3-7) days), CysC levels indicated deterioration of renal function earlier than creatinine did (CysC peaked on day 3, versus day 6 for creatinine), and both stabilized after two weeks. Higher CysC levels, but not creatinine, predicted the endpoint independently of the GRACE score within the first year after index ACS (adjusted HR [95% CI] per 1SD increase: 1.68 [1.03-2.74]). CONCLUSION: Immediately following index ACS, plasma CysC levels deteriorate earlier than creatinine-based indices do, but neither marker stabilizes during hospitalization but on average two weeks after ACS. Serially measured CysC levels predict mortality or recurrence of ACS during 1-year follow-up independently of patients' GRACE risk score.

Trends in comorbidity in patients hospitalised for cardiovascular disease.

BACKGROUND: We determined trends over time in cardiovascular and non-cardiovascular comorbidity in patients hospitalised for cardiovascular disease (CVD). METHODS: The Dutch nationwide hospital register was used to identify patients hospitalised for CVD during 2000-2010. Comorbidity was defined as a previous hospital admission for CVD other than the index CVD, cancer, diabetes, musculoskeletal and connective tissue disorders, respiratory disorders, thyroid gland disorders, kidney disorders and dementia in the five years previous to hospital admittance for the index CVD. Trends were calculated in strata of age and sex and for different types of CVD: coronary heart disease (CHD), cerebrovascular disease (CVA), heart failure (HF) and peripheral arterial disease (PAD). RESULTS: We identified 2,397,773 admissions for CVD between 2000 and 2010. Comorbidity was present in 38%. In HF, PAD, CHD and CVA this was 54%, 46%, 40%, and 32%, respectively. Between 2000 and 2010, the percentage of patients with comorbidity increased (+1.1%), this increase was most pronounced in patients ≥75years (+3.0%). Cardiovascular disease was the most frequent comorbid condition, though became less prevalent over time (men -5%; women: -2%), whereas non-cardiovascular comorbidity increased in men (+4%), and remained similar in women (-1%). Cancer was the most common non-cardiovascular comorbid condition and increased in men and women (men: +5%; women: +4%). CONCLUSIONS: Comorbid conditions are highly prevalent in patients hospitalised for CVD, especially HF and PAD patients. In older patients, prevalences increased over time. Cardiovascular diseases were the most common comorbid condition, though the prevalence decreased over the study period whereas the prevalence of cancer increased.

Cost-effectiveness of screening strategies to detect heart failure in patients with type 2 diabetes.

BACKGROUND: Heart failure (HF), especially with preserved ejection fraction (HFpEF) is common in older patients with type 2 diabetes (T2DM), but often not recognized. Early HF detection in older T2DM patients may be worthwhile because treatment may be initiated in an early stage, with clear beneficial treatment in those with reduced ejection fraction (HFrEF), but without clear prognostic beneficial treatment in those with HFpEF. Because both types of HF may be uncovered in older T2DM, screening may improve health outcomes at acceptable costs. We assessed the cost-effectiveness of five screening strategies in patients with T2DM aged 60 years or over. METHODS: We built a Markov model with a lifetime horizon based on the prognostic results from our screening study of 581 patients with T2DM, extended with evidence from literature. Cost-effectiveness was calculated from a Dutch healthcare perspective as additional costs (Euros) per additional quality-adjusted life-year (QALY) gained. We performed probabilistic sensitivity analysis to assess robustness of these outcomes. Scenario analyses were performed to assess the influence of the availability of effective treatment of heart failure with preserved ejection fraction. RESULTS: For willingness to pay values in the range of €6050/QALY-€31,000/QALY for men and €6300/QALY-€42,000/QALY for women, screening-based checking the electronic medical record for patient characteristics and medical history plus the assessment of symptoms had the highest probability of being cost-effective. For higher willingness-to-pay values, direct echocardiography was the preferred screening strategy. Cost-effectiveness of all screening strategies improved with the increase in effectiveness of treatment for HFpEF. CONCLUSIONS: Screening for HF in older community-dwelling patients with T2DM is cost-effective at the commonly used willingness-to-pay threshold of €20.000/QALY by checking the electronic medical record for patient characteristics and medical history plus the assessment of symptoms. The simplicity of such a strategy makes it feasible for implementation in existing primary care diabetes management programs.

Increased Aortic Valve Calcification in Familial Hypercholesterolemia: Prevalence, Extent, and Associated Risk Factors.

BACKGROUND: Familial hypercholesterolemia is typically caused by LDL receptor (LDLR) mutations that result in elevated levels of LDL cholesterol (LDL-C). In homozygous FH, the prevalence of aortic valve calcification (AoVC) reaches 100% and is often symptomatic. OBJECTIVES: The objective of this study was to investigate the prevalence, extent, and risk-modifiers of AoVC in heterozygous FH (he-FH) that are presently unknown. METHODS: Asymptomatic patients with he-FH and 131 non-familial hypercholesterolemia controls underwent CT computed tomography calcium scoring. AoVC was defined as the presence of calcium at the aortic valve leaflets. The extent of AoVC was expressed in Agatston units, as the AoVC-score. We compared the prevalence and extent of AoVC between cases and controls. In addition, we investigated risk modifiers of AoVC, including the presence of LDLR mutations without residual function (LDLR-negative mutations), maximum untreated LDL-cholesterol (maxLDL), LDL-C, blood pressure, and coronary artery calcification (CAC). RESULTS: We included 145 asymptomatic patients with he-FH (93 men; mean age 52 ± 8 years) and 131 non-familial hypercholesterolemia controls. The prevalence (%) and AoVC-score (median, IQR) were higher in he-FH patients than in controls: 41%, 51 (9-117); and 21%, 21 (3-49) (p < 0.001 and p = 0.007). Age, untreated maxLDL, CAC, and diastolic blood pressure were independently associated with AoVC. LDLR-negative mutational he-FH was the strongest predictor of the AoVC-score (OR: 4.81; 95% CI: 2.22 to 10.40; p = <0.001). CONCLUSIONS: Compared to controls, he-FH is associated with a high prevalence and a large extent of subclinical AoVC, especially in patients with LDLR-negative mutations, highlighting the critical role of LDL-C metabolism in AoVC etiology.

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

Plasma triglyceride levels increase the risk for recurrent vascular events independent of LDL-cholesterol or nonHDL-cholesterol.

BACKGROUND: Plasma triglyceride (TG) levels are known to confer an increased risk of vascular disease in healthy populations, but data in high-risk patients are scarce. In this study we evaluated the risk on recurrent vascular events conferred by increased plasma TG levels in patients with various clinical manifestations of vascular disease. METHODS: Prospective cohort study of 5731 patients with clinically manifest vascular disease. RESULTS: First new vascular events (myocardial infarction, ischemic stroke, vascular death) occurred in 782 subjects during a median follow-up of 4.9 years (interquartile range 2.5-8.1 years). Patients in the highest plasma TG quintile (>2.24 mmol/L) had a higher risk for recurrent vascular events (HR 1.45; 95%CI 1.13-1.86) compared with the lowest plasma TG quintile (<0.97 mmol/L) after adjustments for age, gender, body mass index, smoking, lipid-lowering medication and low-density lipoprotein-cholesterol. The increased risk associated with increasing plasma TG levels was irrespective of the presence of type 2 diabetes (T2DM), but only present in patients without the metabolic syndrome. Furthermore, the increased risk was particularly present in patients with coronary artery disease (CAD) (HR 1.45; 95%CI 1.02-2.08) and was not modified by other lipid levels (p-value for interaction >0.05). Plasma TG still contributed to vascular risk when other lipid levels were at target level. CONCLUSIONS: Higher plasma TG levels are associated with increased risk for recurrent vascular events, in particular in CAD patients. This increased risk is independent of the presence of T2DM and the use of lipid-lowering medication and is not modified by other lipid levels.

Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.

OBJECTIVE: To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia. DESIGN: Cohort study with a mean follow-up of 8.5 years. SETTING: 27 outpatient lipid clinics. SUBJECTS: 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990. MAIN OUTCOME MEASURES: Risk of coronary heart disease in treated and "untreated" (delay in starting statin treatment) patients compared with a Cox regression model in which statin use was a time dependent variable. RESULTS: In January 1990, 413 (21%) of the patients had started statin treatment, and during follow-up another 1294 patients (66%) started after a mean delay of 4.3 years. Most patients received simvastatin (n=1167, 33 mg daily) or atorvastatin (n=211, 49 mg daily). We observed an overall risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30), P<0.001). In fact, the risk of myocardial infarction in these statin treated patients was not significantly greater than that in an age-matched sample from the general population (hazard ration 1.44 (0.80 to 2.60), P=0.23). CONCLUSION: Lower statin doses than those currently advised reduced the risk of coronary heart disease to a greater extent than anticipated in patients with familial hypercholesterolaemia. With statin treatment, such patients no longer have a risk of myocardial infarction significantly different from that of the general population.

Secondary prevention with folic acid: effects on clinical outcomes.

OBJECTIVES: We sought to conduct a randomized trial with folic acid 0.5 mg/day in a patient population with stable coronary artery disease (CAD). BACKGROUND: Folic acid has favorable effects on vascular endothelium and lowers plasma homocysteine levels. In addition, homocysteine appears to be an independent risk factor for atherosclerotic disease. However, the value of folic acid in secondary prevention had seldom been tested. METHODS: In this open-label study, 593 patients were included; 300 were randomized to folic acid and 293 served as controls. Mean follow-up time was 24 months. At baseline all patients had been on statin therapy for a mean of 3.2 years. RESULTS: In patients treated with folic acid, plasma homocysteine levels decreased by 18%, from 12.0 +/- 4.8 to 9.4 +/- 3.5 micromol/l, whereas these levels remained unaffected in the control group (p < 0.001 between groups). The primary end point (all-cause mortality and a composite of vascular events) was encountered in 31 (10.3%) patients in the folic acid group and in 28 (9.6%) patients in the control group (relative risk 1.05; 95% confidence interval: 0.63 to 1.75). In a multifactorial survival model with adjustments for clinical factors, the most predictive laboratory parameters were, in order of significance, levels of creatinine clearance, plasma fibrinogen, and homocysteine. CONCLUSIONS: Within two years, folic acid does not seem to reduce clinical end points in patients with stable coronary artery disease (CAD) while on statin treatment. Homocysteine might therefore merely be a modifiable marker of disease. Thus, low-dose folic acid supplementation should be treated with reservation, until more trial outcomes become available.