Therapeutic quality control in a regional thrombosis center: The effect of changing the target intensity of anticoagulation with vitamin K antagonists.

BACKGROUND: The target ranges (TR) for anticoagulation with vitamin K antagonists (VKA) in the Netherlands were changed in 2016 from INR 2.0-3.5 ('low intensity') and INR 2.5-4.0 ('high intensity') to INR 2.0-3.0 and INR 2.5-3.5, respectively. AIM: To assess the effect of the TR change on therapeutic quality control (TQC) in a Dutch regional thrombosis center taking care of approximately 3600-5500 patients annually. METHODS: TQC of chronically treated patients was assessed as the average time in therapeutic range (TTR). Evaluations were performed for non-self-management (NSM), as well as self-management patients. INR percentiles were assessed from all INR determinations in all patients, i.e. including those of induction episodes and patients treated for a short-term. RESULTS: The number of NSM patients treated chronically decreased gradually, while their average age increased, with a marginal but significant gradual increase in bleeding complications. In the period 2011-2015, i.e. before the TR change, there was a gradual increase of the TTR in NSM patients from 77.5% to 88.9% (low intensity) and from 75.3% to 84.1% (high intensity). In the same period, the median INR of all patients in the low and high intensity ranges decreased from 2.9 to 2.7, and from 3.3 to 3.2, respectively. The TTR in self-management patients remained virtually constant. After TR changes from 2016 on, the TTR of all NSM patients in the low and high intensity groups decreased to 77% and 70%, respectively, and median INRs decreased to 2.6 and 3.0, respectively. CONCLUSIONS: Introduction of internationally harmonized target ranges in 2016 resulted in further lowering of median INR values in both target ranges. As expected, TTR was reduced slightly. These findings, together with a slight increase in average age and concomitant bleeding complications, suggest that the patients on long-term VKA treatment will require intensified monitoring and treatment.

Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes.

OBJECTIVE: The cholesteryl ester transfer protein (CETP) plays a key role in the remodeling of triglyceride (TG)-rich and HDL particles. Sequence variations in the CETP gene may interfere with the effect of lipid-lowering treatment in type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a 30-week randomized double-blind placebo-controlled trial with atorvastatin 10 mg (A10) and 80 mg (A80) in 217 unrelated patients with diabetes. RESULTS: CETP TaqIB and A-629C polymorphisms were tightly concordant (P < 0.001). At baseline, B1B1 carriers had lower plasma HDL cholesterol (0.99 +/- 0.2 vs. 1.11 +/- 0.2 mmol/l, P < 0.05), higher CETP mass (2.62 +/- 0.8 vs. 2.05 +/- 0.4 mg/l, P < 0.001), and slightly increased, though not significant, plasma TGs (2.7 +/- 1.05 vs. 2.47 +/- 0.86, P = 0.34) compared with B2B2 carriers. Atorvastatin treatment significantly reduced CETP mass dose-dependently by 18% (A10) and 29% (A80; both vs. placebo P < 0.001, A10-A80 P < 0.001). CETP mass and activity were strongly correlated (r = 0.854, P < 0.0001). CETP TaqIB polymorphism appeared to modify the effect of atorvastatin on HDL cholesterol elevation (B1B1 7.2%, B1B2 6.1%, B2B2 0.5%; P < 0.05), TG reduction (B1B1 39.7%, B1B2 38.4%, B2B2 18.4%; P = 0.08), and CETP mass reduction (B1B1 32.1%, B1B2 29.6%, B2B2 21.9%; P = 0.27, NS). Similar results were obtained for the A-629C polymorphism. CONCLUSIONS: In conclusion, the B1B1/CC carriers of the CETP polymorphisms have a more atherogenic lipid profile, including low HDL, and they respond better to statin therapy. These results favor the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify patients who will benefit most from statin therapy.

Vascular risk management through nurse-led self-management programs.

In current clinical practice, adequate cardiovascular risk reduction is difficult to achieve. Treatment is primarily focused on clinical vascular disease and not on long-term risk reduction. Pertinent to success in vascular risk reduction are proper medication use, weight control, healthy food choices, smoking cessation, and physical exercise. Atherosclerotic vascular disease and its risk constitute a chronic condition, which poses specific requirements on affected patients and caregivers who should be aware of the chronicity. In patients with vascular disease, there is lack of awareness of their chronic condition because of the invisibility of most risk factors. In other patient groups with chronic illness, self-management programs were successful in achieving behavioral change. This strategy can also be useful for patients with vascular disease to adapt and adhere to an improved lifestyle. Self-management refers to the individual's ability to manage both physical and psychosocial consequences including lifestyle changes inherent to living with a chronic condition. Interventions that promote self-management are based on enhancing self-efficacy. In self-management, attention can be given to what is important and motivational to the individual patient. In this article the challenge of nursing care promoting self-management for patients with vascular risk and how this care can be applied will be explained. Nurses can play a central role in vascular risk management with a self-management approach for patients with chronic vascular disease. In vascular prevention clinics, nursing care can be delivered that includes medical treatment of vascular risks (hypertension, hypercholesterolemia, hyperglycemia, and hyperhomocystinemia) and counseling on promoting self-management (changes in diet, body weight, smoking habits, and level of exercise). Nursing interventions based on self-management promotion can provide a new and promising approach to actually achieve vascular risk reduction.

Does the beneficial effect of HRT on endothelial function depend on lipid changes.

OBJECTIVES: To determine whether improvement in endothelial function of the brachial artery observed in women treated with hormone replacement therapy (HRT) may be explained by changes in lipid profile or blood pressure, information was used obtained in a single-centre, randomised, double blind, placebo-controlled trial. METHODS: Hundred-and-five healthy postmenopausal women, aged 50-65 years, were treated with 0.625 mg conjugated equine estrogens (CEE) combined with 2.5 mg medroxyprogesterone acetate (MPA) (CEE+MPA), 2.5 mg tibolone or placebo for 3 months. At baseline and after 3 months, endothelial function was assessed using flow-mediated dilatation (FMD) and nitro glycerine-mediated dilatation (NMD). Furthermore, lipids were measured. Multivariate linear regression analysis was applied to address the research question. RESULTS: Treatment with CEE+MPA resulted in an improvement in FMD of 2.0% (95% CI: -0.1; 4.1). CEE/MPA reduced total cholesterol with 13% (95% CI: -18%; -7%), LDL-cholesterol with 23% (95% CI: -30%; -15%) and lipoprotein(a) (Lp(a)) with 14% (95% CI: -26%; -2%). The magnitude of the relation of CEE/MPA with endothelial function was attenuated to from 2.0 to 1.6% when change in Lp(a) was taken into account. Adjustments for other lipids or blood pressure did not attenuate the association. CONCLUSIONS: The improvement in endothelial function in postmenopausal women treated with CEE+MPA appears to be partially mediated by change in Lp(a), and apparently not by changes in other lipids.

Atorvastatin affects low density lipoprotein and non-high density lipoprotein cholesterol relations with apolipoprotein B in type 2 diabetes mellitus: modification by triglycerides and cholesteryl ester transfer protein.

OBJECTIVES: Non-HDL-cholesterol (non-HDL-C) and apolipoprotein (apo) B are proposed as treatment targets. The extent to which statin therapy affects relationships of LDL-C and non-HDL-C with apoB was examined in type 2 diabetes. METHODS: Analyses were performed in 217 hypertriglyceridaemic type 2 diabetic patients (Diabetes Atorvastatin Lipid Intervention (DALI) cohort). 61 patients randomized to placebo, 70 to 10 mg atorvastatin daily and 65 - 80 mg atorvastin daily completed follow-up. RESULTS: Baseline fasting LDL-C of 2.42 mmol/l and non-HDL-C of 3.69 mmol/l corresponded to the apoB guideline target of 0.90 g/l. During atorvastatin (10 and 80 mg daily), the LDL-C target was achieved most frequently, and lower LDL-C (2.38 and 2.29 mmol/l) and non-HDL-C (3.24 and 3.19 mmol/l) concentrations corresponded to this apoB goal. Decreases in LDL-C during atorvastatin treatment were negatively related (p < 0.001), but decreases in non-HDL-C were positively related to changes in triglycerides (p < 0.001), independently from decreases in apoB (p < 0.001 for all). Decreases in LDL-C and non-HDL-C were positively associated with decreases in cholesteryl ester transfer protein mass (p < 0.001). CONCLUSIONS: During atorvastatin lower LDL-C and non-HDL-C levels correspond to the apoB guideline target, which would favour its use as treatment target.

Screening for asymptomatic cardiovascular disease with noninvasive imaging in patients at high-risk and low-risk according to the European Guidelines on Cardiovascular Disease Prevention: the SMART study.

OBJECTIVE: To assess the prevalence of atherosclerotic risk factors and to investigate the added value of noninvasive imaging in detecting asymptomatic cardiovascular diseases in patients at low risk and high risk according to the European Guidelines on Cardiovascular Disease Prevention. METHODS: In the vascular screening program of the University Medical Center Utrecht, patients aged 18 to 79 years who had recently received a diagnosis of manifest vascular disease (coronary heart disease, cerebrovascular disease, abdominal aortic aneurysm, or peripheral arterial disease [PAD]) or had a risk factor (hypertension, hyperlipidemia, or diabetes mellitus) were assessed for atherosclerotic risk factors and (other) arterial diseases by noninvasive means. The European guidelines were applied to quantify the number of high-risk patients. RESULTS: Eighty-eight percent of 3950 patients were considered to be at high-risk. More than 80% had hyperlipidemia, approximately 50% had hypertension, 21% had diabetes mellitus, and 31% were current smokers. An asymptomatic reduced ankle-brachial index (< or = 0.90) was most frequently observed in patients with cerebrovascular disease (21%); an asymptomatic abdominal aortic aneurysm (> or = 3.0 cm) in patients with PAD (5%) or cerebrovascular disease (5%); and an asymptomatic carotid stenosis (> or = 50%) in patients with PAD (15%). On the basis of noninvasive measurements, 73 (13%) of 545 patients initially considered as low risk were reclassified as high risk. CONCLUSIONS: This study confirmed a high prevalence and clustering of modifiable atherosclerotic risk factors in high-risk patients. The yield of noninvasive vascular measurements was relatively low but identified a sizable number of high-risk patients. Standard screening for asymptomatic atherosclerotic disease identified a limited number of vascular abnormalities that necessitated immediate medical attention in patients already identified as high-risk patients.

Postmethionine-load homocysteine determination for the diagnosis hyperhomocysteinaemia and efficacy of homocysteine lowering treatment regimens.

Substantial epidemiological evidence supports the vision that moderate hyperhomocysteinaemia is a graded and independent cardiovascular risk factor. The additional value of the methionine loading test for the assessment of hyperhomocysteinaemia continues to be disputed. This overview presents the historical background for the rationale of the methionine loading test and describes determinants and variability of the postmethionine-load homocysteine concentration. The association of postmethionine-load homocysteine concentrations and the risk of cardiovascular events is discussed. Furthermore, the results of homocysteine lowering treatment on postmethionine-load homocysteine are given. Up to 50% of subjects with hyperhomocysteinaemia can only be detected after performing a methionine loading test; these subjects have a normal fasting homocysteine. Both fasting and postmethionine-load homocysteine concentrations are influenced by serum folate and creatinine concentrations and by the methylenetetrahydrofolate reductase genotype, and may be subject to a wide intra-individual variability (approximately 20%). Cross-sectional studies suggest that cardiovascular risk may increase gradually from postmethionine-load homocysteine concentrations above 38 micromol/l. Supplementation with folic acid 0.5 mg daily adequately reduces postmethionine-load homocysteine; addition of pyridoxine appears to have no further homocysteine lowering effect. Prospective studies supporting the clinical significance of the methionine loading test for individual patient counselling are lacking; it seems, therefore, prudent to restrict this test for research purposes.

The metabolic syndrome is associated with advanced vascular damage in patients with coronary heart disease, stroke, peripheral arterial disease or abdominal aortic aneurysm.

AIMS: The metabolic syndrome is associated with an increased risk of cardiovascular disease in patients without a cardiovascular history. We investigated whether the metabolic syndrome is related to the extent of vascular damage in patients with various manifestations of vascular disease. METHODS AND RESULTS: The study population of this cross-sectional survey consisted of 502 patients recently diagnosed with coronary heart disease (CHD), 236 with stroke, 218 with peripheral arterial disease (PAD) and 89 with abdominal aortic aneurysm (AAA). Metabolic syndrome was diagnosed according to Adult Treatment Panel III criteria. Carotid Intima Media Thickness (IMT), Ankle Brachial Pressure Index (ABPI) and albuminuria were used as non-invasive markers of vascular damage and adjusted for age and sex if appropriate. The prevalence of the metabolic syndrome in the study population was 45%. In PAD patients this was 57%; in CHD patients 40%, in stroke patients 43% and in AAA patients 45%. Patients with the metabolic syndrome had an increased mean IMT (0.98 vs 0.92mm, P-value <0.01), more often a decreased ABPI (14% vs 10%, P-value 0.06) and increased prevalence of albuminuria (20% vs 15%, P-value 0.03) compared to patients without this syndrome. An increase in the number of components of the metabolic syndrome was associated with an increase in mean IMT (P-value for trend <0.001), lower ABPI (P-value for trend <0.01) and higher prevalence albuminuria (P-value for trend <0.01). CONCLUSION: In patients with manifest vascular disease the presence of the metabolic syndrome is associated with advanced vascular damage.

A 2-step strategy to reduce the need for methionine-loading tests to diagnose hyperhomocysteinemia.

An increased plasma homocysteine level may increase the risk of cardiovascular disease. The methionine-loading test is commonly used to detect additional subjects with hyperhomocysteinemia who have normal fasting levels of homocysteine but increased post-methionine-load levels. We developed a 2-step strategy to restrict the methionine-loading test to those subjects with intermediate fasting homocysteine levels to confirm the presence of hyperhomocysteinemia. Hyperhomocysteinemia was defined as a fasting plasma homocysteine level of 16.3 micro mol/L or greater in women and 18.8 micro mol/L or greater in men or an increase in plasma homocysteine level after methionine loading of more than 42.3 micro mol/L for both sexes. From the results in 201 patients, 50 years and younger, with manifest atherosclerosis who underwent a methionine-loading test, we derived cutoff points to define an intermediate group of patients who required a methionine-loading test for hyperhomocysteinemia to be ruled out. These cutoff points were validated in a different population of 275 cardiovascular patients of similar age. The prevalence of hyperhomocysteinemia was 30% in the derivation population and 24% in the validation population. To achieve a sensitivity of 90% in diagnosing hyperhomocysteinemia, we set cutoff points of 11.3 and 9.4 micro mol/L for men and women, respectively. When these cutoff points are applied, it is possible to avoid performing the methionine-loading test in 50% to 75% of subjects tested. With a 2-step strategy to diagnose hyperhomocysteinemia, a sensitivity of 90% for the diagnosis of hyperhomocysteinemia can be achieved, and the need for the methionine-loading test is reduced substantially, with 50% to 75% of subjects no longer needing it.

Endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women.

In this study, the authors investigated whether combined information on reproductive factors has additive value to the single reproductive factor age at menopause for assessing endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. They conducted a population-based cohort study that included 9,450 postmenopausal women from Nijmegen, the Netherlands, who were aged 35--65 years at enrollment in 1975, with a median follow-up of 20.5 years. A Cox proportional hazards model and Receiver Operating Curves were used to analyze the data. Women aged 52 years or more at menopause had an 18% reduction in cardiovascular mortality (hazard ratio = 0.82, 95% confidence interval (CI): 0.69, 0.98) compared with those aged 44 years or less. Women with more than 18 years of exposure to endogenous estrogen had a statistically significant 20% reduction in cardiovascular mortality (hazard ratio = 0.80, 95 percent CI: 0.67, 0.96) compared with those who had 13 years of exposure or less. The area under the curve of the Receiver Operating Curves for the two models was identical (area under the curve = 0.67, 95 percent CI: 0.66, 0.68). This study shows that age at menopause is related to cardiovascular disease mortality and that a newly developed composite measure of endogenous estrogen exposure does not add to the predictive value of age at menopause for cardiovascular mortality.