Anglo-Scandinavian Cardiac Outcomes Trial Research Articles

Baseline high sensitivity C-Reactive Protein predicts incident cardiovascular events and all-cause mortality in the ASCOT Study at 20-years

Abstract Introduction The prediction of future cardiovascular events in those at greatest risk is essential to optimise preventative therapies appropriately and effectively. The value of high sensitivity C-reactive Protein (hsCRP) has been questioned in this regard, and recent studies have suggested the utility of this widely assessed biomarker for predicting future mortality in those presenting with suspected myocardial infarction (MI), however the relationship in stable patients is still debated. Purpose To investigate the role of baseline hsCRP for predicting long-term incident cardiovascular events in hypertensive patients in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), with follow-up extending to 20-years. Methods This ASCOT legacy study reports events after 20-years of the UK participants in the original ASCOT trial. ASCOT was a multicentre randomised trial, randomising patients with hypertension into amlodipine-based or atenolol-based blood pressure-lowering (BPL) treatment. In addition, those with total cholesterol <6.5 mmol/L and no previous lipid-lowering treatment underwent further randomisation to either atorvastatin or placebo as part of the lipid-lowering (LL) arm of ASCOT. We examined outcomes related to hsCRP levels in the LL arm, dichotomously (< or > 2mg/L), in tertiles or continuously, adjusting in Model 1 (age, sex, socio-economic status [years of education] and ethnicity) and Model 2 (Model 1 plus current smoker, body mass index, baseline systolic blood pressure, creatinine, diabetes, history of vascular diseases, history of antihypertensive medication and allocation to BPL and LL). All-cause mortality, non-fatal and fatal MI, total coronary events and procedures and total cardiovascular events were assessed. Results 5,294 participants were included in the final cohort, after exclusion of 3,286 participants in the LL arm (n=8,580) without hsCRP data. There were no substantial differences in baseline characteristics between treatment allocation arms (non-randomised, placebo or atorvastatin). The highest tertile of hsCRP (median [IQR], 6.41 [4.81-10.44]) strongly related to all-cause mortality, withstanding adjustment in both Model 1 (HR 95% CI, 1.38 [1.27-1.53]; p<0.001; p<0.001 for interaction) and Model 2 (HR 1.25 [1.10-1.42]; p<0.001; p<0.001 for interaction). Moreover, the highest hsCRP tertile also related to fatal and non-fatal MI (Model 2 – HR 1.32 [1.05-1.67]; p=0.020; p=0.019 for interaction); total coronary events and procedures (Model 2 – HR 1.27 [1.09-1.47]; p=0.002; p=0.003 for interaction); and total cardiovascular events (Model 2 – HR 1.22 [1.08-1.37]; p=0.001; p=0.001 for interaction). Conclusions This study demonstrates that one hsCRP reading at baseline independently predicts cardiovascular events and all-cause mortality at very long-term follow-up in patients at high-risk for these events, and may help stratify patients into higher risk categories for intensive preventative strategies.

Tissue Doppler E prime velocity and E/E prime predict 19-year cardiovascular mortality in hypertension

Abstract Background We have previously shown that tissue Doppler assessments of left ventricular (LV) diastolic function predict cardiac events in a hypertensive population over a period of 4 years (1). These out-performed traditional echocardiographic measures in a well-treated hypertensive population. Purpose We aimed to test whether tissue Doppler assessment of LV diastolic function would predict cardiovascular (CV) mortality in the Hypertension Associated Cardiovascular Disease sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Methods ASCOT was a multicentre randomised trial with a 2x2 factorial design (2). Inclusion criteria for the study included hypertension and three other CV risk factors, including male sex and age over 55. Protocols, including for echocardiography, have been detailed previously (2, 3). This study comprised the 519 patients recruited to the St Mary's Hospital site of the ASCOT study, who were followed for 19 years with mortality flagged by the Office for National Statistics. We have used all reported deaths on or before 31st January 2019. CV deaths include deaths due to coronary heart disease (CHD), stroke and other CV causes. Echocardiography was performed one year after blood pressure control. mean tissue Doppler E' was calculated as the average of septal, lateral and inferior wall measurements over three cycles. The ratio of the transmitral Doppler E wave velocity and the composite mean of E' was used to calculate E/E' ratio. Statistical analysis was performed using Python including multivariable Cox proportional hazards regression. A two-sided P-value <0.05 was considered statistically significant. Results After a median of 19 years, 317 patients survived (mean age at baseline 60.7y, 38 female) and 202 did not (mean age 68.1y, 30 female). Twenty-three deaths were due to CHD, 11 were due to stroke, 27 were due to other CV causes, and 76 were due to cancer. Baseline characteristics were not significantly different between those who survived to follow up and those who did not. Unadjusted analysis showed a strong association between CV mortality and E' (HR=0.74, p<0.005) and E/E' (HR=1.18, p<0.005) (Table 1). The association between CV mortality and E' was attenuated slightly but persisted after adjusting for age and sex (HR=0.83, p=0.02) and after adjusting for age, sex and systolic BP (HR=0.83, p=0.03). The association between CV mortality and E/E' was attenuated but persisted after adjusting for age and sex (HR=1.12, p=0.01) and after adjusting for age, sex and systolic BP (HR=1.11, p=0.04). There was a weak association between all-cause mortality and both E/E' and E', which was null after adjusting for age and sex. Figure 1 shows unadjusted Kaplan Meier survival curves for E'. Conclusions Tissue Doppler E' velocity and E/E' predicted 19-year cardiovascular mortality in a hypertensive population independent of age, sex and systolic blood pressure. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The HACVD substudy was supported by an investigational grant by Pfizer International, New York, NY, USA. The principal funding source for ASCOT was Pfizer, New York, NY, USA, additional funding was also provided by Servier Research Group, Paris, France, and Leo Laboratories, Copenhagen, Denmark.

Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial

In patients with hypertension, the long-term cardiovascular and all-cause mortality effects of different blood pressure-lowering regimens and lipid-lowering treatment are not well documented, particularly in clinical trial settings. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study reports mortality outcomes after 16 years of follow-up of the UK participants in the original ASCOT trial. ASCOT was a multicentre randomised trial with a 2 × 2 factorial design. UK-based patients with hypertension were followed up for all-cause and cardiovascular mortality for a median of 15·7 years (IQR 9·7-16·4 years). At baseline, all patients enrolled into the blood pressure-lowering arm (BPLA) of ASCOT were randomly assigned to receive either amlodipine-based or atenolol-based blood pressure-lowering treatment. Of these patients, those who had total cholesterol of 6·5 mmol/L or lower and no previous lipid-lowering treatment underwent further randomisation to receive either atorvastatin or placebo as part of the lipid-lowering arm (LLA) of ASCOT. The remaining patients formed the non-LLA group. A team of two physicians independently adjudicated all causes of death. Of 8580 UK-based patients in ASCOT, 3282 (38·3%) died, including 1640 (38·4%) of 4275 assigned to atenolol-based treatment and 1642 (38·1%) of 4305 assigned to amlodipine-based treatment. 1768 of the 4605 patients in the LLA died, including 903 (39·5%) of 2288 assigned placebo and 865 (37·3%) of 2317 assigned atorvastatin. Of all deaths, 1210 (36·9%) were from cardiovascular-related causes. Among patients in the BPLA, there was no overall difference in all-cause mortality between treatments (adjusted hazard ratio [HR] 0·90, 95% CI 0·81-1·01, p=0·0776]), although significantly fewer deaths from stroke (adjusted HR 0·71, 0·53-0·97, p=0·0305) occurred in the amlodipine-based treatment group than in the atenolol-based treatment group. There was no interaction between treatment allocation in the BPLA and in the LLA. However, in the 3975 patients in the non-LLA group, there were fewer cardiovascular deaths (adjusted HR 0·79, 0·67-0·93, p=0·0046) among those assigned to amlodipine-based treatment compared with atenolol-based treatment (p=0·022 for the test for interaction between the two blood pressure treatments and allocation to LLA or not). In the LLA, significantly fewer cardiovascular deaths (HR 0·85, 0·72-0·99, p=0·0395) occurred among patients assigned to statin than among those assigned placebo. Our findings show the long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin: patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure. Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes. Pfizer.

Genetic variants in PPARGC1B and CNTN4 are associated with thromboxane A2 formation and with cardiovascular event free survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

Background and aimsElevated urinary 11-dehydro thromboxane B2 (TxB2), a measure of thromboxane A2 formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB2 and their associations with cardiovascular morbidity were investigated in this study. MethodsGenome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants. ResultsThe strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB2 formation. Haplotypes of 11-dehydro TxB2 increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB2, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p=0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB2 were individually associated with greater incidences of cardiovascular events - rs10515638 (HR = 1.31, p=0.01) and rs10510230 (HR = 1.25, p=0.007); effect sizes were larger in those not taking aspirin. ConclusionsPPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention.

LB.03.08] SERUM CHLORIDE AND ADVERSE CARDIOVASCULAR EVENTS IN THE ANGLO SCANDINAVIAN CARDIAC OUTCOMES TRIAL (ASCOT)

Objective: Data suggests that lower serum chloride (Cl-) is associated with higher mortality and cardiovascular risk in populations with hypertension or heart failure. In this study, we tested the association between serum Cl- and cardiovascular outcomes in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Blood Pressure-Lowering Arm. Design and method: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized a subset of 6549 patients at risk with no history of coronary heart disease to either atenolol-based or amlodipine-based BP lowering treatment and followed-up for 5.5 years. Serum Cl- was measured at baseline in 319 participants who had a cardiovascular event and 1361 controls, matched for age and sex. The primary outcome was a composite of fatal and non-fatal myocardial infarction, stroke and heart failure. Subjects were grouped into four categories based on Serum Cl- levels (Cl-< = 95; 95.1–105; 105.1–115; >115.1 mmol/L). The characteristics of the study population across these groups were compared using 1-way ANOVA for continuous variables and X2 test for categorical variables. Kaplan-Meier (KM) and Cox Proportional Hazard models (Cox-PH), adjusted for age, sex, body mass index, systolic blood pressure, smoking, diabetes, cholesterol, serum Na+, use of diuretics and randomisation group, were used to explore the multivariate adjusted association between baseline serum Cl- and cardiovascular events. Results: Participants with Cl- <95 mmol/L had a greater proportion of females (24.1 vs 11.9%; p 0.02) than those with Cl- >115.1, were slightly older (67.8[7.7] vs 65.3[7.5] years; p 0.01), had lower sodium (139[5] vs 142[3] mmol/L; p <0.01), and were more likely to be taking a diuretic (66.3 vs 28.9%; p < 0.01). Serum Cl- <95 mmol/L was associated with an increased risk of a cardiovascular event (HR 4.09[95% CI 1.17–14.32; p 0.03] independent of serum Na+ (1.01[0.97–1.5]; p 0.80) or diuretic use (1.13[0.89–1.42]; p 0.31) compared to those with serum Cl->115.1 mmol/L (figure). Conclusions: In the ASCOT study, serum chloride less than 95 mmol/L was associated with greater risk of cardiovascular events, independent of serum sodium or diuretic use.

Circulating Apolipoprotein E Concentration and Cardiovascular Disease Risk: Meta-analysis of Results from Three Studies.

BackgroundThe association of APOE genotype with circulating apolipoprotein E (ApoE) concentration and cardiovascular disease (CVD) risk is well established. However, the relationship of circulating ApoE concentration and CVD has received little attention.Methods and FindingsTo address this, we measured circulating ApoE concentration in 9,587 individuals (with 1,413 CVD events) from three studies with incident CVD events: two population-based studies, the English Longitudinal Study of Ageing (ELSA) and the men-only Northwick Park Heart Study II (NPHSII), and a nested sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). We examined the association of circulating ApoE with cardiovascular risk factors in the two population-based studies (ELSA and NPHSII) and the relationship between ApoE concentration and coronary heart disease and stroke in all three studies. Analyses were carried out within study, and, where appropriate, pooled effect estimates were derived using meta-analysis. In the population-based samples, circulating ApoE was associated with systolic blood pressure (correlation coefficient 0.08, p < 0.001, in both ELSA and NPHSII), total cholesterol (correlation coefficient 0.46 and 0.34 in ELSA and NPHSII, respectively; both p < 0.001), low-density lipoprotein cholesterol (correlation coefficient 0.30 and 0.14, respectively; both p < 0.001), high-density lipoprotein (correlation coefficient 0.16 and −0.14, respectively; both p < 0.001), and triglycerides (correlation coefficient 0.43 and 0.46, respectivly; both p < 0.001). In NPHSII, ApoE concentration was additionally associated with apolipoprotein B (correlation coefficient 0.13, p = 0.001) and lipoprotein(a) (correlation coefficient −0.11, p < 0.001). In the pooled analysis of ASCOT, ELSA, and NPHSII, there was no association of ApoE with CVD events; the odds ratio (OR) for CVD events per 1-standard-deviation higher ApoE concentration was 1.02 (95% CI 0.96, 1.09). After adjustment for cardiovascular risk factors, the OR for CVD per 1-standard-deviation higher ApoE concentration was 0.97 (95% CI 0.82, 1.15). Limitations of these analyses include a polyclonal method of ApoE measurement, rather than isoform-specific measurement, a moderate sample size (although larger than any other study to our knowledge and with a long lag between ApoE measures), and CVD events that may attenuate an effect.ConclusionsIn the largest study to date on this question, we found no evidence of an association of circulating ApoE concentration with CVD events. The established association of APOE genotype with CVD events may be explained by isoform-specific functions as well as other mechanisms, rather than circulating concentrations of ApoE.

High Serum Immunoglobulin G and M Levels Predict Freedom From Adverse Cardiovascular Events in Hypertension: A Nested Case-Control Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

AimsWe aimed to determine whether the levels of total serum IgM and IgG, together with specific antibodies against malondialdehyde-conjugated low-density lipoprotein (MDA-LDL), can improve cardiovascular risk discrimination. Methods and ResultsThe Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized 9098 patients in the UK and Ireland into the Blood Pressure-Lowering Arm. 485 patients that had cardiovascular (CV) events over 5.5years were age and sex matched with 1367 controls. Higher baseline total serum IgG, and to a lesser extent IgM, were associated with decreased risk of CV events (IgG odds ratio (OR) per one standard deviation (SD) 0.80 [95% confidence interval, CI 0.72,0.89], p<0.0001; IgM 0.83[0.75,0.93], p=0.001), and particularly events due to coronary heart disease (CHD) (IgG OR 0.66 (0.57,0.76); p<0.0001, IgM OR 0.81 (0.71,0.93); p=0.002). The association persisted after adjustment for a basic model with variables in the Framingham Risk Score (FRS) as well as following inclusion of C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NtProBNP). IgG and IgM antibodies against MDA-LDL were also associated with CV events but their significance was lost following adjustment for total serum IgG and IgM respectively. The area under the receiver operator curve for CV events was improved from the basic risk model when adding in total serum IgG, and there was improvement in continuous and categorical net reclassification (17.6% and 7.5% respectively) as well as in the integrated discrimination index. ConclusionHigh total serum IgG levels are an independent predictor of freedom from adverse cardiovascular events, particularly those attributed to CHD, in patients with hypertension.

Variabilty of arterial pressure and renal function

This review deals with variability of arterial pressure (VAP) as an advers factor contributing to the development andprogression of cardiovascular diseases and renal pathology. VAP has recently attracted much attention in connection with results of ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) showing that VAP is a risk factor of stroke and other complications of arterial hypertension (A H). The relationship between VAP and renalfunction remains unexplored and is considered to be a vicious circle in which kidneys are both a cause of AH and its target organs. Evidently elucidation of the relationship between enhanced VAP and renal function is of primay importance.

Combination therapy in the extended cardiovascular continuum: a focus on perindopril and amlodipine.

The progression of cardiovascular disease could be regarded as following atherosclerosis-related and age-related pathways. The starting points for these pathways are different--risk factors or aortic ageing--but they conclude in the same way: end-stage heart disease. Together these interlinked pathways form the extended cardiovascular continuum. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been shown to interrupt or slow the progression of cardiovascular disease along one pathway, the cardiovascular atherosclerotic continuum. Cardiovascular protection with RAAS inhibitors varies; different RAAS inhibitors offer different levels of protection. Similarly, calcium channel blockers (CCBs) also have clearly shown protective effect of cardiovascular system, especially as it regards cerebrovascular disease risk. The AngloScandinavian Cardiac Outcomes Trial (ASCOT) showed that a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and CCB amlodipine offered better cardiovascular protection in at-risk hypertensive patients than beta-blocker and thiazide. By attenuating the deleterious effects of cardiovascular disease at multiple stages of the extended cardiovascular continuum on top of lowering blood pressure (BP), perindopril and amlodipine could interrupt and slow the progression of cardiovascular disease. These antihypertensive agents have complementary vascular effects that enhance cardiovascular protection and reduce side-effects. Evidence from ASCOT shows that antihypertensive and vascular effects of amlodipine with and without perindopril have translated into real-life clinical benefits. A strategy using ACE inhibitors and CCBs, such as perindopril and amlodipine, to target multiple stages in both pathways of cardiovascular disease could effectively reduce cardiovascular risk and lower BP.

Impact of Female Sex on Lipid Lowering, Clinical Outcomes, and Adverse Effects in Atorvastatin Trials

The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.

Combination of Statin Plus Renin Angiotensin System Inhibition for the Prevention or the Treatment of Atherosclerotic Cardiovascular Disease

Statins effectively reduce cardiovascular disease (CVD) morbidity and mortality. However, even after low-density lipoprotein cholesterol goal attainment there is a residual CVD risk. To reduce this risk, combining statins with drugs acting on the renin-angiotensin system (RAS) was investigated. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE), Japanese Coronary Artery Disease (JCAD), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and The Assessing the Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) trials suggest that the statin plus RAS inhibition combination reduces CVD events more than a statin alone and considerably more than RAS inhibition alone. This benefit seems to be related to effects on endothelial function, vascular inflammation and the initiation, progression and rupture of atheromatous plaques. These effects are, at least in part, driven by mediators, the microRNAs (miRs), that are implicated in the pathogenesis and clinical manifestations of atherosclerosis (e.g. restoration of endothelial function and attenuation of vascular inflammation). Some miRs are favourably affected by statins and others by RAS inhibition. There is a miR family (miR-146a/b), related to coronary artery plaque destabilization that is beneficially affected by both statins and RAS inhibition. Statins and RAS inhibition combination should be routinely prescribed in high risk patients with CVD, hypertension, obesity, metabolic syndrome, and/or diabetes to maximize clinical benefit.

Excess Pressure Integral Predicts Cardiovascular Events Independent of Other Risk Factors in the Conduit Artery Functional Evaluation Substudy of Anglo-Scandinavian Cardiac Outcomes Trial

Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular events and target organ damage in treated hypertensive individuals. Radial blood pressure waveforms were acquired by tonometry in 2069 individuals (aged, 63±8 years) in the Conduit Artery Functional Evaluation (CAFE) substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Measurements of left ventricular mass index (n=862) and common carotid artery intima media thickness (n=923) were also performed. XSPI and the integral of reservoir pressure were lower in people treated with amlodipine±perindopril than in those treated with atenolol±bendroflumethiazide, although brachial systolic blood pressure was similar. A total of 134 cardiovascular events accrued during a median 3.4 years of follow-up; XSPI was a significant predictor of cardiovascular events after adjustment for age and sex, and this relationship was unaffected by adjustment for conventional cardiovascular risk factors or Framingham risk score. XSPI, central systolic blood pressure, central augmentation pressure, central pulse pressure, and integral of reservoir pressure were correlated with left ventricular mass index, but only XSPI, augmentation pressure, and central pulse pressure were associated positively with carotid artery intima media thickness. Associations between left ventricular mass index, XSPI, and integral of reservoir pressure and carotid artery intima media thickness and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of cardiovascular dysfunction and independently predicts cardiovascular events and targets organ damage in a prospective clinical trial.

Natriuretic Peptide: A Probable Culprit in Prevention of Primary Cardiovascular Diseases Using β-Blockers

This letter refers to “The Value of N-Terminal Pro-B-Type Natriuretic Peptide in Determining Antihypertensive Benefit: Observations From the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)” by Welsh et al1 The 2014 evidence-based guideline for the management of high blood pressure in adults from the Eighth Joint National Committee (JNC …

Editorial: Do We Have Effective Means to Treat Arterial Stiffness and High Central Aortic Blood Pressure in Patients with and without Hypertension?

The reduction or loss of arterial elasticity or distensibility leads to arterial stiffness (AS), which has a substantial predictive value for all-cause and cardiovascular disease (CVD) mortality, as well as for non-fatal CVD events [1]. A plethora of evidence consistently showed the prognostic value of aortic stiffness for fatal and nonfatal CVD events in various populations at different levels of CVD risk, including the general population, elderly subjects and patients with hypertension, type 2 diabetes mellitus (T2DM) and end-stage renal disease (ESRD) [2]. It has been reported that 1-SD increase in pulse wave velocity (PWV) is associated with a 47% increase in the risk for total mortality [95% confidence interval (CI), 1.31-1.64] and a similar 47% increase in the risk for CVD mortality (95% CI, 1.29-1.66) [2].

The Value of N-Terminal Pro–B-Type Natriuretic Peptide in Determining Antihypertensive Benefit

We investigated 3 hypotheses: (1) N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts cardiovascular disease events in patients with hypertension, (2) NT-proBNP is associated with blood pressure variability, and (3) NT-proBNP predicts benefit from antihypertensive regimens. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized a subset of 6549 patients at risk with no history of coronary heart disease to either atenolol-based or amlodipine-based blood pressure-lowering treatment. During 5.5 years of follow-up, 485 cardiovascular disease cases accrued and were matched with 1367 controls. Baseline and 6-month in-trial NT-proBNP were measured. The results show that NT-proBNP improves cardiovascular disease risk prediction beyond established predictors, continuous net reclassification improvement of 22.3% (P<0.0001). Furthermore, a 1-mm Hg increase in the SD of systolic blood pressure was associated with 2% higher baseline NT-proBNP in a multivariable regression analysis (P<0.0001). However, NT-proBNP predicted cardiovascular disease risk independently of blood pressure variation (odds ratio per SD increase in log NT-proBNP 1.24; 95% confidence interval, 1.06-1.45; P=0.007). Atenolol-based treatment led to a 69.6% increase in NT-proBNP at 6 months (P<0.0001). In contrast, amlodipine-based treatment reduced NT-proBNP by 36.5% (P<0.0001). Amlodipine recipients who achieved a 6-month NT-proBNP below the median (61 pg/mL) were at lower risk of cardiovascular disease when compared with those who did not (odds ratio, 0.58; 95% confidence interval, 0.37-0.91) after adjustment for confounders inclusive of baseline NT-proBNP and achieved blood pressure. If confirmed, these novel results suggest that NT-proBNP, as well as aiding cardiovascular disease risk assessment, may also help assess the efficacy of specific antihypertensive regimens. Further relevant studies seem warranted.

Dissecting the protective IgG anti-malondialdehyde-LDL (MDA-LDL) antibody response in a substudy of the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT)

Purpose: To elucidate associations between high LDL-C in children of patients with PCAD (onset ≤55 years, men; ≤60 years, women) and some their own and parental characteristics. Methods: We examined members of 122 families with children aged 5-17 years: 111 parents-probands (83.8% men, aged 32-56 years, 84.7% after MI), their 103 consorts (12.6% men, aged 28-63 years, 1% with overt CAD) and 152 their own children (63.2% men, aged 5-17 years). We registered weight at birth, breast feeding duration, habits, body mass index (BMI), waist circumference (WC), heart rate (HR), systolic (S)/diastolic BP, total/high density lipoprotein (HDL) C, LDL-C, triglycerides (TG), glucose, glucose tolerance, diabetes, arterial pre/hypertension (NHBPEP-4 criteria) and (in parents) education, menstruation status, metabolic syndrome (MS, JIS criteria). In persons aged 5-17 years high LDLC was defined as ≥90 percentile (Lipid Research Clinics). Predictors of high LDLC were selected by age, sex adjusted logistic regression. Results: High LDL-C was found in 42/152 (27.6%) of children. Characteristics related to the presence of high LDL-C with p<0.1 in univariate analysis (BMI, WC, TG, SBP, weight at birth, HDL-C of children; LDL-C, HR, non-smoking of proband; LDL-C, non-smoking of consort) were included into stepwise regression procedure. Independent predictors of high LDL-C were own BMI; LDL-C, HR of proband; LDL-C, non-smoking of consort (table).

Evaluation of C-Reactive Protein Before and On-Treatment as a Predictor of Benefit of Atorvastatin: A Cohort Analysis From the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm

The aim of this study was to determine whether baseline and on-statin C-reactive protein (CRP) are independent predictors of cardiovascular (CV) outcome beyond low-density lipoprotein cholesterol (LDL-C). Use of CRP as a predictor of statin treatment remains controversial. We investigated the relationship of baseline and on-treatment CRP with subsequent CV events in Cox models using a subset of white subjects with no history of CV disease from the UK ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). During 5.5 years of follow-up, a total of 488 subjects experienced a CV event. CV risk increased with baseline CRP (hazard ratio [HR] per 1 SD: 1.21; 95% confidence interval [CI]: 1.09 to 1.33) in an adjusted model. In ASCOT Lipid-Lowering Arm, the relative statin effect in preventing CV events did not differ according to tertiles of baseline CRP (p= 0.69). After 6 months of atorvastatin therapy, the median LDL-C and CRP were reduced by 38.7% and 25.8%, respectively. Those who achieved LDL-C below the median had a reduced CV risk (HR: 0.58; 95% CI: 0.34 to 0.97) compared with those who did not. In contrast, those who achieved a CRP level below the median did not have a reduced risk of CV events (HR: 0.95; 95% CI: 0.59 to 1.55). Among those who achieved LDL-C below the median, there was no difference in CV risk whether they also achieved a CRP level below (HR: 0.55; 95% CI: 0.30 to 1.02) or above the median (HR: 0.56; 95% CI: 0.30 to 1.03). In these primary prevention patients, although baseline CRP independently predicted CV event risk, the achieved CRP level on while statin therapy did not predict CV events, either alone or in combination with LDL-C.

Recent Clinical Trials of Hypertension Management

The scene for clinical trials of hypertension management is in transition. The era of mega trials may not be over but is certainly in decline, and in the past 2 years there have been no studies reporting primary outcome data the scale of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and other major studies that marked clinical trial activity and informed guideline committees during the past 2 to 3 decades. This reflects in part the view that the present benchmark pharmacological agents for treating hypertension are difficult to improve, some systemic issues affecting the pharmaceutical industry influencing the ability to make the large investment required to perform mega trials and the quality of the antihypertensive drug pipeline. Together these considerations have tended to drive interest toward equivalence rather than efficacy studies (ie, trials designed to show an investigational agent is as good as, not better than, existing treatment), surrogate end points, including new blood pressure (BP) variables, and studies of combinations and algorithms rather than single interventions. Population studies around the world, however, continue to show that large numbers of people have hypertension that is not treated satisfactorily and are not achieving the goals set by the major national guidelines. These guidelines themselves are under continual scrutiny on the basis of recent data casting doubt on the validity of present BP goals. Guideline committees also face the issue that evidence based on expensive large-scale clinical trials is more often funded by the pharmaceutical or device industries than by government, leaving large evidence gaps in areas of public importance but no direct interest to industry funders. The purpose of the present article is to briefly review clinical trials of …

Is plasma renin activity a biomarker for the prediction of renal and cardiovascular outcomes in treated hypertensive patients? Observations from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

Plasma renin activity (PRA) has been shown to predict future cardiovascular (CV) events in observational studies and in clinical trials and to be associated with the prevalence of chronic renal disease in hypertensive subjects. In a nested case-control study, we explored the relationship between CV and renal outcomes and all-cause mortality with baseline measurements of PRA among hypertensive adults randomized in the ASCOT trial. In the UK and Ireland, ASCOT included 9098 hypertensive adults randomized to either calcium channel blocker (CCB)- or β-blocker (BB)-based treatment. Four thousand eight hundred and fifty-three patients with total cholesterol ≤6.5 mmol/L (250 mg/L) were further randomized to atorvastatin or placebo. Over 5.5 years, there were 399 CV events (fatal coronary heart disease (CHD), non-fatal myocardial infarction, coronary revascularization, and fatal and non-fatal stroke), 96 cases of new-onset renal impairment, and 220 deaths. Cases were age, sex, and ethnicity matched with 1525 controls. Conditional logistic regression models were used to evaluate the association between CV events, renal impairment, all-cause mortality, and PRA. For those on antihypertensive (AHT) treatment at the baseline (91.5%), PRA was influenced by prior drug treatment. The median (inter-quartile range; ng/mL/h) levels were 1.04 (0.52, 1.3) for BBs, 1.30 (0.78, 2.72) for CCBs, 1.56 (0.91, 3.50) for diuretics, and 2.33 (1.30, 5.57) for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Odds ratios (OR) and 95% confidence intervals (CIs) for CV and other events were estimated for 1-SD increase in log-transformed PRA levels and by categorizing PRA into quartiles with the lowest as the referent category. Baseline PRA did not predict CV events in models adjusted for baseline characteristics [OR 0.92 (CI 0.81, 1.06, P = 0.25)] and for pre-randomized AHT treatment [OR 0.91 (CI 0.79, 1.04, P = 0.17)] and was not associated with all-cause mortality [OR 1.12 (CI 0.92, 1.37, P = 0.25) and OR 1.06 (CI 0.91, 1.24, P = 0.46)] in the fully adjusted model. Baseline levels of PRA were positively but non-significantly associated with the development of renal impairment in models adjusted for baseline characteristics [OR 1.39 (CI 0.97, 1.97, P = 0.07)] and also for pre-randomized antihypertensive (AHT) treatment [OR 1.35 (CI 0.95, 1.94, P = 0.10)]. Quartile analyses, however, demonstrated a significant positive association of higher levels of PRA with the development of impaired renal function (P = 0.03 and 0.05 in adjusted models, respectively) compared with the lowest quartile. These analyses suggest an association between elevated baseline PRA and the subsequent development of renal impairment but do not support its use to predict future CV events or all-cause mortality in treated hypertensive patients without diagnosed CHD.

9 IgG anti-malonedialdehyde-LDL antibodies are associated with low risk of cardiovascular events in a substudy of the anglo-scandinavian cardiac outcomes trial (Ascot), and are unrelated To LDL, CRP levels and statin treatment

BackgroundWe aimed to determine whether measurement of antibodies to modified LDL predicts cardiovascular events.MethodsWe studied ASCOT participants without diabetes with total cholesterol of ≤6.5 mmol/l and a total cholesterol/HDL ratio...