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.

AIMS: We 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 RESULTS: The 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. CONCLUSION: High total serum IgG levels are an independent predictor of freedom from adverse cardiovascular events, particularly those attributed to CHD, in patients with hypertension.

The value of N-terminal pro-B-type natriuretic peptide in determining antihypertensive benefit: observations from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

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.

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.

OBJECTIVES: 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). BACKGROUND: Use of CRP as a predictor of statin treatment remains controversial. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

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).

AIMS: 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. METHODS AND RESULTS: In the UK and Ireland, ASCOT included 9098 hypertensive adults randomized to either calcium channel blocker (CCB)- or ß-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. CONCLUSION: 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.

Evaluation of C-reactive protein prior to and on-treatment as a predictor of benefit from atorvastatin: observations from the Anglo-Scandinavian Cardiac Outcomes Trial.

AIMS: We tested whether on-statin C-reactive protein is associated with cardiovascular (CV) outcome in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). METHODS AND RESULTS: ASCOT randomized a subset of 4853 patients with total cholesterol ≤6.5 mmol/L (250 mg/dL) to atorvastatin or placebo. In a case-control study during 5.5-year follow-up, 485 CV cases were age- and sex-matched with 1367 controls. Baseline LDL-cholesterol (LDL-c) and log-transformed C-reactive protein predicted CV events [odds ratio (OR) per 1 standard deviation (SD) 1.31 (95% confidence interval {CI}: 1.10, 1.56), P = 0.002 and OR 1.19 (1.05, 1.34), P = 0.006, respectively]. Including baseline C-reactive protein into a Framingham risk model very modestly improved risk prediction. Baseline C-reactive protein did not indicate the magnitude of the atorvastatin effect on CV outcome (P = 0.54). At 6 months, atorvastatin reduced median LDL-c by 40.3% and median C-reactive protein by 27.4%. In those randomized to atorvastatin, lower on-treatment LDL-c at 6 months was associated with a significant reduction in subsequent CV events [OR 0.41 (0.22, 0.75), P = 0.004] comparing those above and below the median (2.1 mmol/L). In contrast, C-reactive protein below the median (1.83 mg/L) compared with C-reactive protein above the median was not associated with a significant reduction in CV events [OR 0.86 (0.49, 1.51), P = 0.60]. Consequently, addition of on-treatment C-reactive protein to LDL-c did not improve prediction of statin efficacy. CONCLUSION: Among these hypertensive patients selected on the basis of traditional CV risk factors, C-reactive protein did not usefully improve the prediction of CV events and, critically, reduction in C-reactive protein associated with statin therapy was not a predictor of CV outcome alone or in combination with LDL-c.

Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk.

BACKGROUND: Resistant hypertension is a well recognized clinical entity, which has been inadequately researched to date. METHODS: A multivariable Cox model was developed to identify baseline predictors of developing resistant hypertension among 3666 previously untreated Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) patients and construct a risk score to identify those at high risk. Secondary analyses included evaluations among all 19 257 randomized patients. RESULTS: One-third (1258) of previously untreated, and one-half (9333) of all randomized patients (incidence rates 75.2 and 129.7 per 1000 person-years, respectively) developed resistant hypertension during a median follow-up of 5.3 and 4.8 years, respectively. Increasing strata of baseline SBP (151-160, 161-170, 171-180, and >180 mmHg) were associated with increased risk of developing resistant hypertension [hazard ratio 1.24 (95% confidence interval, CI 0.81-1.88), 1.50 (1.03-2.20), 2.15 (1.47-3.16), and 4.43 (3.04-6.45), respectively]. Diabetes, left ventricular hypertrophy, male sex, and raised BMI, fasting glucose, and alcohol intake were other significant determinants of resistant hypertension. Randomization to amlodipine ±â€Šperindopril vs. atenolol ±â€Šthiazide [0.57 (0.50-0.60)], previous use of aspirin [0.78 (0.62-0.98)], and randomization to atorvastatin vs. placebo [0.87 (0.76-1.00)] significantly reduced the risk of resistant hypertension. Secondary analysis results were similar. The risk score developed allows accurate risk allocation (Harrell's C-statistic 0.71), with excellent calibration (Hosmer-Lemeshow χ statistics, P = 0.99). A 12-fold (8.4-17.4) increased risk among those in the highest vs. lowest risk deciles was apparent. CONCLUSION: Baseline SBP and choice of subsequent antihypertensive therapy were the two most important determinants of resistant hypertension in the ASCOT population. Individuals at high risk of developing resistant hypertension can be easily identified using an integer-based risk score.

The Anglo-Scandinavian Cardiac Outcomes Trial: 11-year mortality follow-up of the lipid-lowering arm in the U.K.

AIMS: The aim of this study was to determine the outcome benefits in those originally assigned atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial-8 years after closure of the lipid-lowering arm (LLA) of the trial (ASCOT-LLA) among the U.K. population. METHODS AND RESULTS: ASCOT-LLA was a factorially designed double-blind placebo-controlled trial of atorvastatin in 10 305 hypertensive patients enrolled into the ASCOT-Blood Pressure Lowering Arm (BPLA) of the trial and with total cholesterol concentrations, at baseline, of <6.5 mmol/L. ASCOT-LLA was stopped prematurely after a median 3.3-year follow-up because of a 36% relative risk reduction (RRR) in non-fatal myocardial infarction and fatal coronary heart disease (CHD) (the primary outcome) in favour of atorvastatin and a non-significant reduction in CV deaths (16%) and all-cause mortality (13%). After a further 2.2 years at the end of ASCOT-BPLA, despite extensive crossovers from and to statin usage, the RRR in all endpoints remained essentially unchanged. A median 11 years after initial randomization and ∼8 years after closure of LLA, all-cause mortality (n=520 and 460 in placebo and atorvastatin, respectively) remained significantly lower in those originally assigned atorvastatin (HR 0.86, CI 0.76-0.98, P=0.02). CV deaths were fewer, but not significant (HR 0.89, CI 0.72-1.11, P=0.32) and non-CV deaths were significantly lower (HR 0.85, CI 0.73-0.99, P=0.03) in those formerly assigned atorvastatin attributed to a reduction in deaths due to infection and respiratory illness. CONCLUSION: Legacy effects of those originally assigned atorvastatin may contribute to long-term benefits on all-cause mortality. An explanation for long-term benefits on non-CV deaths has not been established.