A Methodology for Mapping the Patient Journey for Noncommunicable Diseases in Low- and Middle-Income Countries.

Noncommunicable diseases (NCDs) are responsible for 71% of all worldwide mortality each year, and have an exceptionally large impact in low- and middle-income countries (LMICs). However, there is often a lack of local data from these countries to inform practice and policy improvements. Generating locally contextualized evidence base for NCDs that can help identify gaps, aid decision-making and improve patient care in LMICs needs an innovative approach. The approach used in Mapping the Patient Journey Towards Actionable Beyond the Pill Solutions (MAPS) is designed to quantitatively map different stages of the patient journey in four critical NCDs, ie, hypertension, dyslipidemia, depression, and pain (chronic and neuropathic) across selected LMICs in Africa, the Middle East, South East Asia, and Latin America. The key touchpoints along the patient journey include awareness, screening, diagnosis, treatment, adherence, and control or remission. MAPS employs an evidence mapping methodology that follows a three-step semi-systematic review: 1) systematic peer-reviewed database search; 2) unstructured searches of local or real-world data; and 3) expert opinion. Evidence generation and visualization is based on locally validated and deduplicated data published over the last 10 years. This approach will be the first to provide quantitative mapping of the different stages of the patient journey for selected NCDs in LMICs. By focusing on local, patient-centric data, the goal of the MAPS initiative is to address and prioritize local research and knowledge gaps, then contribute to evidence-based, high-quality, and affordable advances in the management of NCDs in LMICs. This will ultimately improve patient outcomes and contribute towards the achievement of global NCD targets.

Systemic Solutions for Addressing Non-Communicable Diseases in Low- and Middle-Income Countries.

Non-communicable diseases (NCDs) have been on the rise in low- and middle-income countries (LMICs) over the last few decades and represent a significant healthcare concern. Over 85% of "premature" deaths worldwide due to NCDs occur in the LMICs. NCDs are an economic burden on these countries, increasing their healthcare expenditure. However, targeting NCDs in LMICs is challenging due to evolving health systems and an emphasis on acute illness. The major issues include limitations with universal health coverage, regulations, funding, distribution and availability of the healthcare workforce, and availability of health data. Experts from across the health sector in LMICs formed a Think Tank to understand and examine the issues, and to offer potential opportunities that may address the rising burden of NCDs in these countries. This review presents the evidence and posits pragmatic solutions to combat NCDs.

Relationship of Inter-Individual Blood Pressure Variability and the Risk for Recurrent Stroke.

Background Evidence suggests that patients with higher blood pressure variability ( BPV ) have a higher risk for stroke, but any link between BPV and stroke recurrence is unknown among those who had a stroke or transient ischemic attack ( TIA ). Methods and Results Data for patients with a history of stroke or TIA at enrollment were extracted from the ASCOT (Anglo Scandinavian Cardiac Outcomes Trial) and the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). BPV was defined as the within-subject standard deviation or coefficient of variation of systolic blood pressure across visits from 12 weeks poststroke or TIA onward. BPV was significantly higher in patients with a history of stroke or TIA than those without. BPV was a predictor of recurrent stroke in the pooled analysis. In the ASCOT study, 252 patients (12.3%) had a recurrent stroke among 2046 with a history of stroke. Incidence of recurrent stroke was significantly higher in the highest BPV quartile (17.8%) compared with the lowest quartile (10.5%); by treatment arm, this reached significance for the amlodipine-arm only (high- BPV : 18.7% versus low- BPV : 12.9%; P=0.029). Of the 2173 patients from the ALLHAT with a history of stroke or TIA , patients with the highest quartile of BPV had a higher incidence of recurrent stroke (9.6%) compared with the lowest quartile BPV (5.5%); by treatment arm, this reached significance for the chlorthalidone-arm only (high- BPV : 12.1% versus low- BPV : 5.4%; P=0.007). Conclusions Visit-to-visit BPV is a predictor of recurrent stroke in patients with a history of stroke or TIA on antihypertensive treatment. Considering BPV following a stroke may be important to reduce the risk for a recurrent stroke.

Relationship Between Visit-to-Visit Blood Pressure Variability (BPV) and Kidney Function in Patients with Hypertension.

BACKGROUND/AIMS: To investigate the impact of kidney function (using estimated glomerular filtration rate, [eGFR]) on blood pressure variability (BPV) via a retrospective post hoc analysis of patients with hypertension enrolled in two large clinical trials. METHODS: Subject-level data were extracted from ASCOT (N=18,852) and ALLHAT (N=26,441) databases; both were randomized, active controlled studies, with treatment duration for hypertension ≥4 years. Visit-to-visit BPV was assessed using the square root of the coefficient of variation of systolic blood pressure (SBP) across visits from 12 weeks onwards. Baseline GFR, estimated by the simplified Modification of Diet in Renal Disease equation, was stratified into ≤60, 61-90, and >90 mL/min/1.73 m2. The relationship between baseline eGFR and systolic BPV was analyzed using an analysis of covariance, with baseline factors considered as covariates. Studies were pooled and analyzed individually. RESULTS: Patient characteristics were largely consistent between studies. In the pooled population (n=38,133) there were 19.1%, 62.9%, and 18.0% patients, with eGFR ≤60, 61-90, and > 90 mL/min/1.73 m2, respectively. Patients with lower baseline eGFR had higher systolic BPV, in the pooled population and the individual analyses. Other baseline predictors of high systolic BPV included high SBP and age, being male, and a smoker. An amlodipine-based regimen was a negative predictor of high systolic BPV, vs. other antihypertensives, regardless of eGFR. CONCLUSIONS: Patients with declining renal function tended to have higher systolic BPV vs. those without, even after adjusting for risk factors. Amlodipine-based therapy reduced BPV more than other antihypertensive agents, regardless of level of eGFR.

Predictors of visit-to-visit blood pressure variability in patients with hypertension: an analysis of trials with an amlodipine treatment arm.

We conducted a post hoc analysis of blood pressure (BP) data from long-term antihypertensive trials to identify predictors of visit-to-visit BP variability (BPV). BPV was defined as the within-subject coefficient of variation in systolic BP from week 12 onward. BP data from the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis, NY92011, and R-0510 trials were pooled and dichotomized into top 25th and bottom 75th percentiles because of positive skew. Significant (P < .001) predictors of BPV within the top 25th percentile were identified using logistic regression. The baseline characteristics of the pooled cohort (n = 47,558) were similar between patients who received amlodipine (n = 17,499) versus other antihypertensive drugs (n = 29,491). BPV in the top 25th percentile was lower with amlodipine versus other treatments (13.7 ± 3.2 vs. 14.3 ± 3.5), with single-study analyses of Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis all showing BPV was the lowest with amlodipine. Baseline diastolic BP, estimated glomerular filtration rate, and smoking were predictors of BPV, with significant two-way interactions between smoking and both age and body mass index and between systolic BP or diastolic BP and being randomized to treatment other than amlodipine. In conclusion, analysis of BPV required transformation of BP data. After transformation, a number of baseline variables and combinations of variables were predictors of BPV.

Effect of inter-individual blood pressure variability on the progression of atherosclerosis in carotid and coronary arteries: a post hoc analysis of the NORMALISE and PREVENT studies.

Aims: To investigate the relationship between visit-to-visit blood pressure variability (BPV) and the progression of both carotid and coronary artery disease (CAD). Methods and results: Data from two cardiovascular endpoint studies [Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation (NORMALISE) and Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT)] were analysed separately. Systolic BPV was assessed as within-subject standard deviation of systolic BP across visits from 12-weeks onwards. Follow-up was 24 months (NORMALISE) or 36 months (PREVENT). Any association between BPV and progression of atherosclerosis was assessed using quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), or B-mode ultrasound (depending on study). Patients from NORMALISE (n = 261) and PREVENT (n = 688 for QCA; n = 364 for ultrasound) were stratified within study according to median systolic BPV. No significant difference in change of minimal luminal diameter (by QCA in PREVENT) or change in percent atheroma volume or normalized total atheroma volume (by IVUS in NORMALISE) was detected for subjects with low BPV (BPV < median) compared with high BPV (BPV ≥ median), regardless of treatment. In PREVENT, a significantly greater reduction in maximum carotid intima-media thickness (IMT) (left and right common carotid artery far wall) was observed for patients with BPV < median compared with those with BPV ≥ median [least squares mean difference 0.06 (95% confidence interval 0.01, 0.11); P = 0.0271], after adjusting for treatment, carotid artery segment (left or right), baseline maximum carotid IMT, and other baseline and cardiovascular risk factors/covariates. Conclusions: In patients with existing CAD and well-controlled BP, visit-to-visit BPV was not associated with progression of coronary atherosclerosis; however, a significantly greater reduction in maximum carotid IMT was observed for patients with low BPV.

Efficacy of Calcium Channel Blockers Versus Other Classes of Antihypertensive Medication in the Treatment of Hypertensive Patients With Previous Stroke and/or Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Hypertensive patients, such as those with established coronary artery disease (CAD) or those who have suffered a stroke, are at increased risk of morbidity and mortality. This systematic literature review and meta-analysis assesses the long-term effects of calcium channel blockers (CCBs) compared with other classes of antihypertensive medications on major cardiovascular (CV) outcomes in these high-risk subgroups of hypertensive patients. Randomized, active controlled parallel group trials were included if they compared CCBs with α-blockers, ß-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, or diuretics, had a follow-up of ≥6 months, and had assessments of blood pressure (BP) and CV events [all-cause death, CV death, major CV events (myocardial infarction, MI; congestive heart failure, CHF; stroke; and CV death), MI, stroke, or CHF] in patients with baseline systolic/diastolic BP ≥140/≥90 mm Hg with either concomitant previous stroke and/or CAD. The final dataset included 19 publications reporting on 7 unique trials. In hypertensive patients with previous stroke, there was no difference between CCBs and comparators for any CV outcome. In those with CAD, there was no difference for all-cause death, CV death, major CV events, and MI for CCBs relative to comparators; however, a reduction in the risk of stroke and an increase in the risk of CHF were seen. For BP lowering, CCBs were at least as efficacious as comparators. The findings of our systematic review and analysis add to the body of evidence for the use of CCBs for the long-term treatment of hypertension in difficult-to-treat high CV risk populations.

Effect of visit-to-visit blood pressure variability on cardiovascular events in patients with coronary artery disease and well-controlled blood pressure.

This post hoc analysis of CAMELOT and PREVENT analyzed the impact of blood pressure variability (BPV, assessed as within-subject standard deviation of SBP from 12 weeks onward) on the incidence of major adverse cardiovascular events (MACE, defined according to original studies). Patients (n = 1677 CAMELOT; n = 776 PREVENT) were stratified by BPV quartile. Regardless of study, BPV was significantly lower for amlodipine versus other treatments. In CAMELOT, a significant association between BPV quartile and MACE was observed with amlodipine treatment. Significant associations between BPV quartile and MACE were observed for both studies, when analyzed overall (adjusting for treatment). In CAMELOT, with amlodipine treatment, an increased risk for MACE was observed with high (BPV ≥ Q3) versus low BPV (< Q1; adjusting for characteristics and risk factors). In both studies, increased risk for MACE was observed for BPV ≥ Q3 versus BPV < Q1 (analyzed overall, adjusting for treatment and covariates). For both studies, BPV, but not mean SBP, was associated with cardiovascular events. BPV was associated with cardiovascular outcomes in patients with CAD and well-controlled BP.

A Systematic Review on the Efficacy of Amlodipine in the Treatment of Patients With Hypertension With Concomitant Diabetes Mellitus and/or Renal Dysfunction, When Compared With Other Classes of Antihypertensive Medication.

The long-term cardiovascular (CV) effects of calcium channel blockers, with special focus on amlodipine, were compared with other classes of antihypertensive medications in high-risk hypertensive patient subgroups. A systematic literature review and meta-analysis was undertaken of 38 unique randomized, active-controlled, parallel-group trials comparing amlodipine/calcium channel blockers with diuretics, ß-blockers, α-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers, with ≥6-month follow-up, and which had included assessment of blood pressure (BP) and CV events [all-cause death, CV death, myocardial infarction (MI), stroke, congestive heart failure (CHF), or major CV events (MACE: MI, CHF, stroke, and CV death)], in hypertensive patients (baseline systolic/diastolic BP ≥140/≥90 mm Hg) with either concomitant diabetes and/or renal dysfunction. In hypertensive patients with diabetes, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, and MI; a decrease in stroke risk, and an increase in CHF risk, was seen. In hypertensive patients with renal dysfunction, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, MI, and CHF; a decrease in stroke risk was seen. Amlodipine was found to be at least as efficacious as all the other classes of antihypertensive agents in reducing systolic and diastolic BP. Long-term control of BP is critical for avoiding complications of hypertension in high-risk patients, particularly CV and cerebrovascular events such as stroke. This analysis has provided evidence that amlodipine is an appealing therapeutic option in the long-term management of hypertension in both diabetic and renal dysfunction patients.

Incremental Blood Pressure-Lowering Effect of Titrating Amlodipine for the Treatment of Hypertension in Patients Including Those Aged ≥55 Years.

Small reductions in blood pressure reduce the risk of cardiovascular events. Here, we report 2 post hoc pooled analyses assessing the antihypertensive effect of amlodipine in patients who had not responded to 5 mg and were uptitrated to 10 mg. The first analysis assessed subgroups of patients aged either younger than 55 years or 55 years or older and the second analysis pooled all patients irrespective of age. Of 706 patients in the age-related analysis, a statistically significant decrease in blood pressure from baseline was observed {for younger than 55 years [N = 253]: systolic blood pressure = -12.8 [standard error (SE) = 0.90] mm Hg, diastolic blood pressure = -8.0 [SE = 0.55] mm Hg; for 55 years or older [N = 453]: systolic blood pressure = -12.1 [SE = 0.66] mm Hg, diastolic blood pressure = -6.7 [SE = 0.39] mm Hg; all P < 0.0001}. In total, 45.8% and 39.3% of patients aged younger than 55 and 55 years or older, respectively, achieved their blood pressure goals. Adverse events were experienced by 62 (24.5%) patients aged younger than 55 years and 136 (30.0%) patients aged 55 years or older. Similar efficacy and safety results were seen in the all patient pooled analysis. Titration of amlodipine from 5 mg to 10 mg significantly decreased blood pressure in older hypertensive patients, which is clinically relevant because increased age is associated with hypertension and cardiovascular events.

Uptitrating amlodipine significantly reduces blood pressure in diabetic patients with hypertension: a retrospective, pooled analysis.

Diabetic patients with hypertension are approximately twice as likely to develop cardiovascular disease as non-diabetic patients with hypertension. Given that hypertension affects ∼60% of patients with diabetes, effective blood pressure (BP) management is important in this high-risk population. This post-hoc analysis pooled data from six clinical studies to quantify additional BP efficacy achieved when titrating hypertensive diabetic patients from amlodipine 5 mg to 10 mg. Approximately half of the diabetic patients were male (44/98; 44.9%) with a mean (standard deviation [SD]) age of 60.6 (9.6) years and a baseline mean (standard error [SE]) systolic blood pressure/diastolic blood pressure (SBP/DBP) of 150.8 (1.30)/87.5 (0.94) mmHg while on amlodipine 5 mg (159.1 [1.40]/92.6 [0.94] mmHg prior to treatment). In comparison, 350/610 (57.4%) non-diabetic patients were male with a mean (SD) age of 58.7 (11.1) years and baseline mean (SE) SBP/DBP of 150.3 (0.62)/90.9 (0.41) mmHg while on amlodipine 5 mg (160.0 [0.67]/96.2 [0.45] mmHg prior to treatment). Increasing amlodipine from 5 mg to 10 mg lowered sitting SBP by -12.5 mmHg (95% confidence interval (CI): -15.5, -9.5; P<0.0001) and DBP by -6.0 mmHg (-7.4, -4.6; P<0.0001) in diabetic patients; and SBP by -12.4 mmHg (-13.5, -11.3; P<0.0001) and DBP by -7.3 mmHg (-8.0, -6.7; P<0.0001) in non-diabetic patients. In total, 12.0% (95% CI: 6.4, 20.0) of diabetic patients achieved their BP goal versus 46.4% (42.4, 50.4) of non-diabetic patients after titration to amlodipine 10 mg. Overall, 22.0% of diabetic patients experienced 31 adverse events (AEs) and 28.9% of non-diabetic patients experienced 282 AEs. Serious AEs were reported by one (1.0%) diabetic and five (0.8%) non-diabetic patients. In this analysis, increasing amlodipine from 5 mg to 10 mg produced a clinically significant reduction in the BP of diabetic hypertensive patients, similar to non-diabetic patients, highlighting the importance of optimizing amlodipine titration in this high-risk population.

Effects of amlodipine and other classes of antihypertensive drugs on long-term blood pressure variability: evidence from randomized controlled trials.

Blood pressure (BP) is monitored and managed to prevent cardiovascular complications of hypertension, but BP variability (BPV) has not been sufficiently studied. This analysis assessed whether patients receiving amlodipine vs other antihypertensive agents had lower BPV after ≥12 weeks of treatment. Studies were included if individual subject data were available, had ≥1 active comparator, and treatment duration was ≥12 weeks. BPV was assessed using standard deviation (SD) and coefficient of variation (CV) of systolic BP across visits from 12 weeks. Individual trial and meta-analyses were performed for SD- and CV-based methodology. Five studies (47,558 BPV-evaluable patients) were included. Patient characteristics were largely consistent across the studies, but BP measurements varied from ∼4 months to ∼6 years. BPV with amlodipine was significantly (P < .0001) lower vs atenolol and lisinopril; significantly (P < .0001) lower than enalapril in one study and numerically, but not significantly lower in another; and similar to chlorthalidone and losartan. Meta-analysis revealed a treatment difference (standard error) for amlodipine vs all active comparators of -1.23 (0.46; P = .008) mm Hg using SD and -0.86 (0.31; P = .005) using CV. These findings suggest that amlodipine is effective for minimizing BPV. Future studies need to confirm a causal link between BPV and cerebrovascular/cardiovascular outcomes.

Pharmacokinetics of a novel orodispersible tablet of sildenafil in healthy subjects.

BACKGROUND: Sildenafil citrate is indicated for the treatment of erectile dysfunction. An orally disintegrating tablet (ODT) of sildenafil citrate has been developed for the benefit of patients who have difficulty swallowing solid dosage forms. OBJECTIVE: The main goal of this study was to evaluate the bioequivalence of sildenafil ODT with and without water versus marketed sildenafil oral film-coated tablets. A secondary objective was to evaluate the effects of a high-fat meal on the pharmacokinetics of sildenafil ODT. METHODS: The bioequivalence study of sildenafil ODT given with and without water versus marketed sildenafil citrate film-coated oral tablets was conducted in 36 subjects. In a food-effect study, the effect of a standard high-fat meal on the pharmacokinetics of sildenafil ODT was evaluated in 12 subjects. Both studies were randomized, open-label, crossover, single-dose (50 mg) studies in healthy men aged ≥45 years. Plasma samples were collected for 14 hours postdose, and pharmacokinetics were determined by using noncompartmental analyses. RESULTS: All subjects in both studies were Asian males between the ages of 45 and 69 years. Sildenafil ODT without water was bioequivalent to the marketed sildenafil film-coated oral tablet as the 90% CI for the ratio of geometric means of Cmax, AUC0-∞, and AUC0-last were contained within equivalence limits (80%-125%). When sildenafil ODTs were given with water, the 90% CIs for sildenafil AUC0-∞ and AUC0-last were contained within the range of 80% to 125%; however, the 90% CI for sildenafil Cmax was not (79.76-92.78). This difference in Cmax is unlikely to have any clinically meaningful impact. High-fat meals reduced the rate but not the extent of absorption of sildenafil. Mean Cmax was reduced by 59%, and median Tmax was delayed from 0.625 hour (fasting) to 4 hours (high-fat meal). However, AUC values were comparable between fed and fasted treatments. CONCLUSIONS: Sildenafil ODT, given with or without water, provides equivalent systemic exposure compared with marketed sildenafil film-coated oral tablets, thus offering a convenient alternative method of administration. Considering the results of the food-effect study, sildenafil ODT should be taken on an empty stomach. ClinicalTrials.gov identifiers: NCT01254383 (bioequivalence) and NCT01254396 (food effect).

Titration of amlodipine to higher doses: a comparison of Asian and Western experience.

In this retrospective analysis, data pooled from two Phase III/IV open-label Asian studies were used to quantify the additional blood pressure efficacy achieved when titrating amlodipine from 5 mg to 10 mg in mild/moderate hypertensive patients, and compared to data pooled from three Western studies. The primary efficacy end point was the change from baseline in sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) to the specified time point (4-8 weeks, depending on the trial). For the Asian analysis (n=174), both mean SBP and DBP were significantly decreased at the final visit (SBP -13.3 mmHg, 95% confidence interval [CI] -15.5 to -11.0; DBP -9.2 mmHg, 95% CI -10.6 to -7.8; both P<0.0001). These results were similar to the Western analysis (n=369; SBP -11.5 mmHg, 95% CI -13.1 to -10.0; DBP -6.3, 95% CI -7.1 to -5.5; both P<0.0001). In summary, titration of amlodipine from 5 mg to 10 mg significantly decreased both SBP and DBP in Asian patients with mild-to-moderate hypertension.

A large observational study of cardiovascular outcomes associated with atorvastatin or simvastatin therapy in hypertensive patients without prior cardiovascular disease.

The objective of this study was to examine whether differences in effectiveness exist between statins in hypertensive patients seen in clinical practice. We assessed cardiovascular (CV) outcomes in hypertensive patients without cardiovascular disease who began therapy with atorvastatin (10 or 20 mg/d) or simvastatin (20 or 40 mg/d) between January 1, 2003, and September 30, 2005, using claims data from 92 US managed care plans in the PharMetrics database. A total of 98,471 hypertensive patients were identified, comprising 74,685 atorvastatin users (mean dose 13.6 mg/d) and 23,786 simvastatin users (mean dose 28.6 mg/d), and followed a median 1.5 years for the occurrence of a first CV event. The crude CV event rates were 2.81 and 3.92 per 100 person-years for atorvastatin and simvastatin, respectively [unadjusted hazard ratio (HR): 0.73; 95% confidence interval (CI): 0.68-0.78, P < 0.001]. After adjusting for clinical and demographic confounders, use of atorvastatin was associated with fewer CV events compared with simvastatin (HR: 0.91; 95% CI: 0.84-0.98, P = 0.009). However, the lipid-lowering efficacy of the 2 statins could not be assessed as patient lipid data were unavailable. In conclusion, hypertensive patients without cardiovascular disease who initiated atorvastatin (10 or 20 mg/d) had a significantly lower risk of subsequent CV events compared with those who initiated simvastatin at doses of similar potency (20 or 40 mg/d). As with all observational studies, the study is subject to certain limitations, and the findings should be regarded as hypothesis generating.

A large observational study of cardiovascular outcomes associated with atorvastatin or simvastatin therapy in diabetic patients without prior cardiovascular disease.

Analysis of claims data from 46,076 diabetic patients without cardiovascular disease initiating atorvastatin or simvastatin therapy suggested that, after adjusting for demographic and clinical confounders, use of atorvastatin was associated with fewer cardiovascular events versus simvastatin at doses of similar potency (HR 0.88, 95% CI 0.80-0.97, P=0.01).

Circulating lipid hydroperoxides predict cardiovascular events in patients with stable coronary artery disease: the PREVENT study.

OBJECTIVES: This study was designed to determine the predictive value of lipid hydroperoxide (LOOH) levels for adverse cardiovascular outcomes in patients with stable coronary artery disease (CAD). BACKGROUND: Oxidative modification of circulating lipids contributes to inflammation and endothelial dysfunction, which are hallmark features of atherosclerosis. A serum biomarker of oxidation is LOOH, which is a primary product of fatty acid peroxidation. METHODS: Serum LOOH levels were measured and correlated with clinical events over a 3-year period in 634 patients with angiographic evidence of CAD. RESULTS: Baseline LOOH levels in the highest quartile were associated with hazard ratios of 3.24 (95% confidence interval [CI] 1.86 to 5.65; p = 0.0001) for nonfatal vascular events (n = 149), 1.80 (95% CI 1.13 to 2.88; p = 0.014) for major vascular procedures (n = 139), and 2.23 (95% CI 1.44 to 3.44; p = 0.0003) for all vascular events and procedures. Baseline LOOH levels correlated with serum levels of soluble intercellular adhesion molecule-1 (p = 0.001) and thiobarbituric acid reactive substances (p = 0.001) as well as the mean percent change in stenosis for large segments >50% stenosed (p = 0.048). A multivariate proportional hazards model, adjusted for traditional risk factors and inflammatory markers, showed an independent effect of LOOH on nonfatal vascular events, vascular procedures, and all events or procedures. Amlodipine treatment was associated with reduced cardiovascular events and changes in LOOH levels compared with placebo. CONCLUSIONS: Elevated LOOH levels were predictive of nonfatal vascular events and procedures in patients with stable CAD, independent of traditional risk factors and inflammatory markers.

Serum levels of thiobarbituric acid reactive substances predict cardiovascular events in patients with stable coronary artery disease: a longitudinal analysis of the PREVENT study.

OBJECTIVES: The objective of this study was to test the predictive value of an oxidative stress biomarker in 634 patients from the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT). BACKGROUND: Oxidative stress contributes to mechanisms of atherosclerosis and plaque instability. Biomarkers of oxidation, such as malondialdehyde (MDA), may represent independent indicators of risk for patients with stable coronary artery disease (CAD). METHODS: Serum MDA levels were measured as thiobarbituric acid reactive substances (TBARS) in 634 patients with documented CAD using reverse-phase high-performance liquid chromatography and spectrophotometric approaches. RESULTS: During the three-year study, there were 51 major vascular events such as fatal/nonfatal myocardial infarction, 149 hospitalizations for nonfatal vascular events, and 139 patients underwent a major vascular procedure. At baseline, patients with TBARS levels in the highest quartile had a relative risk (RR) of 3.30 (95% confidence interval [CI] 1.47 to 7.42; p = 0.038) for major vascular events, RR of 4.10 (95% CI 2.55 to 6.60; p < 0.0001) for nonfatal vascular events, and RR of 3.84 (95% CI 2.56 to 5.76; p < 0.0001) for major vascular procedures. The effect of TBARS on events and procedures was also seen in a multivariate model adjusted for inflammatory markers (C-reactive protein, soluble intercellular adhesion molecule-1, interleukin-6), and other risk factors (age, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, body mass index, and blood pressure). This analysis showed an independent effect of TBARS on major vascular events (p = 0.0149), nonfatal vascular events (p < 0.0001), major vascular procedures (p < 0.001), and all vascular events and procedures (p < 0.0001). CONCLUSIONS: Serum levels of TBARS were strongly predictive of cardiovascular events in patients with stable CAD, independently of traditional risk factors and inflammatory markers.

Insulin resistance during puberty and future fat accumulation.

Insulin resistance is a known sequela of obesity; however, the relationship of insulin resistance to future weight gain remains unclear. In several studies, insulin resistance has been associated with weight stabilization. For the most part, this relationship has been found in adults who are overweight. To evaluate the relationship of insulin resistance to future fat accumulation in pubertal children, a 3-yr prospective study was carried out. Insulin sensitivity (Si) was determined by Bergman's minimal model in 111 healthy children, aged 9.7-14.5 yr. All children were Tanner stage II or III pubertal development at baseline. Body composition was assessed by body mass index, skinfold thickness, hydrodensitometry, and bioelectric impedance analysis at baseline and annually thereafter for an additional 3 yr. A repeated-measures analysis showed that the change in percentage body fat estimated from skinfold thickness [%BF(SF)] over time changed with increasing Si (P < 0.0001). Si was divided into tertiles for each gender, with the lowest tertile representing the most insulin-resistant children. For girls, those in the lowest tertile maintained their %BF(SF) over 3 yr, whereas those girls in the middle and upper tertile had an increase in their %BF(SF). For boys, those in the lowest tertile showed a decrease in their %BF(SF), whereas those boys in the middle and upper tertile maintained their %BF(SF). These results suggest that during puberty, children who are more insulin resistant have decreased sc fat gain.