Carotid atherosclerosis progression in familial hypercholesterolemia patients: a pooled analysis of the ASAP, ENHANCE, RADIANCE 1, and CAPTIVATE studies.

BACKGROUND: Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression. METHODS AND RESULTS: We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies. In the 3 recent studies combined, mean cIMT increased at only 33%of the rate of the simvastatin-treated patients in the ASAP study (0.014 mm/2 years [95% confidence interval, -0.0003-0.028] versus 0.041 mm/2 years [95% confidence interval, 0.020-0.061]; P<0.05). Patients whose statin therapy could be intensified, as evidenced by an LDL-C decrease after the initiation of on-trial statin therapy, showed cIMT decrease in the first 6 to 12 months and a much lower cIMT increase measured over the full 2 years. In line with this, previously statin-naive HeFH patients showed a lower overall cIMT increase. CONCLUSIONS: Over the years, intensification of statin therapy in HeFH patients has resulted in an impressive decrease in carotid atherosclerosis progression. In studies that assess other antiatherosclerotic modalities, statin therapy may still induce rapid changes in cIMT. For future cIMT studies, our analyses suggest that patient populations other than intensively pretreated HeFH patients should be selected and that the statin regimen should not be changed on study initiation.

Relation of different measures of low-density lipoprotein cholesterol to risk of coronary artery disease and death in a meta-regression analysis of large-scale trials of statin therapy.

Multiple randomized controlled trials (RCTs) have established the efficacy of statins for the prevention of cardiovascular disease. The benefits observed are often framed in terms of percentage reductions in low-density lipoprotein (LDL) cholesterol from baseline or percentage reductions between control and treatment groups, although epidemiologic data suggest that the absolute intergroup difference in LDL cholesterol (DeltaLDL(Control-Rx)) is the more informative measure. A systematic review of large-scale trials of statins versus placebo, usual care, or active (lower dose statin) control was conducted to calculate updated summary estimates of risk reduction in coronary artery disease and all-cause mortality. Meta-regression analysis was used to ascertain the relations of different LDL cholesterol metrics to outcomes. In 20 eligible RCTs, there were significant overall reductions for coronary artery disease (odds ratio 0.72, 95% confidence interval 0.67 to 0.78) and mortality (odds ratio 0.89, 95% confidence interval 0.84 to 0.94), but with substantial variability in trial results. DeltaLDL(Control-Rx) was the strongest determinant of coronary artery disease risk reduction, particularly after excluding active-comparator studies, and was independent of baseline LDL cholesterol. In contrast, baseline LDL cholesterol edged out DeltaLDL(Control-Rx) as the strongest determinant of mortality, but neither was significant after the exclusion of active-comparator studies. The exclusion of 3 RCTs involving distinct populations, however, rendered DeltaLDL(Control-Rx) the predominant determinant of mortality reduction. In conclusion, these findings underscore the primacy of absolute reductions in LDL cholesterol in the design and interpretation of RCTs of lipid-lowering therapies and in framing treatment recommendations on the basis of the proved coronary benefits of these drugs.

Effects of sources of variability on sample sizes required for RCTs, applied to trials of lipid-altering therapies on carotid artery intima-media thickness.

OBJECTIVE: Studies measuring progression of carotid artery intima-media thickness (cIMT) have been used to estimate the effect of lipid-modifying therapies cardiovascular event risk. The likelihood that future cIMT clinical trials will detect a true treatment effect is estimated by leveraging results from prior studies. The present analyses assess the impact of between- and within-study variability based on currently published data from prior clinical studies on the likelihood that ongoing or future cIMT trials will detect the true treatment effect of lipid-modifying therapies. METHODS: Published data from six contemporary cIMT studies (ASAP, ARBITER 2, RADIANCE 1, RADIANCE 2, ENHANCE, and METEOR) including data from a total of 3563 patients were examined. Bayesian and frequentist methods were used to assess the impact of between study variability on the likelihood of detecting true treatment effects on 1-year cIMT progression/regression and to provide a sample size estimate that would specifically compensate for the effect of between-study variability. RESULTS: In addition to the well-described within-study variability, there is considerable between-study variability associated with the measurement of annualized change in cIMT. Accounting for the additional between-study variability decreases the power for existing study designs. In order to account for the added between-study variability, it is likely that future cIMT studies would require a large increase in sample size in order to provide substantial probability (> or =90%) to have 90% power of detecting a true treatment effect.Limitation Analyses are based on study level data. Future meta-analyses incorporating patient-level data would be useful for confirmation. CONCLUSION: Due to substantial within- and between-study variability in the measure of 1-year change of cIMT, as well as uncertainty about progression rates in contemporary populations, future study designs evaluating the effect of new lipid-modifying therapies on atherosclerotic disease progression are likely to be challenged by large sample sizes in order to demonstrate a true treatment effect.

Flushing profile of extended-release niacin/laropiprant versus gradually titrated niacin extended-release in patients with dyslipidemia with and without ischemic cardiovascular disease.

Niacin has beneficial effects on a patient's lipid and lipoprotein profiles and cardiovascular risk, particularly at doses >2 g/day, but is underused due to flushing. Laropiprant (LRPT), a selective prostaglandin D(2) receptor-1 antagonist, decreases flushing associated with extended-release niacin (ERN). We compared flushing with ERN/LRPT dosed by a simplified 1-g --> 2-g regimen versus gradually titrated niacin extended-release (N-ER; given as NIASPAN, trademark of Kos Life Sciences LLC). Patients with dyslipidemia (n = 1,455) were randomized 1:1 to ERN/LRPT (1 g for 4 weeks advanced to 2 g for 12 weeks) or N-ER (0.5 g for 4 weeks titrated in 0.5-g increments every 4 weeks to 2 g for the final 4 weeks). Aspirin/nonsteroidal anti-inflammatory drugs were allowed to mitigate flushing. Flushing severity was assessed using the validated Global Flushing Severity Score (GFSS; none 0, mild 1 to 3, moderate 4 to 6, severe 7 to 9, extreme 10). Patients on ERN/LRPT, despite more rapid niacin titration, had less flushing than those on N-ER, as measured by number of days per week with moderate or greater GFSS across the treatment period (p <0.001). More than 2 times as many patients had no episodes of moderate, severe, or extreme flushing (GFSS > or =4) with ERN/LRPT than with N-ER (47.0% vs 22.0%, respectively) across the treatment period. Fewer patients on ERN/LRPT discontinued due to flushing than those on N-ER (7.4% vs 12.4%, p = 0.002). Other than the decrease in flushing, the safety and tolerability profile of ERN/LRPT was similar to that of N-ER. In conclusion, improvement in flushing with ERN/LRPT versus gradually titrated N-ER supports a rapidly advanced 1-g --> 2-g dosing regimen, allowing patients to start at 1 g and quickly reach and tolerate the optimal 2 g dose of ERN.

Lipid changes during the menopause transition in relation to age and weight: the Study of Women's Health Across the Nation.

Few studies have prospectively examined lipid changes across the menopause transition or in relation to menopausal changes in endogenous hormones. The relative independent contributions of menopause and age to lipid changes are unclear. Lipid changes were examined in relation to changes in menopausal status and in levels of estradiol and follicle-stimulating hormone in 2,659 women followed in the Study of Women's Health Across the Nation (1995-2004). Baseline age was 42-52 years, and all were initially pre- or perimenopausal. Women were followed annually for up to 7 years (average, 3.9 years). Lipid changes occurred primarily during the later phases of menopause, with menopause-related changes similar in magnitude to changes attributable to aging. Total cholesterol, low density lipoprotein cholesterol, triglycerides, and lipoprotein(a) peaked during late peri- and early postmenopause, while changes in the early stages of menopause were minimal. The relative odds of low density lipoprotein cholesterol (> or =130 mg/dL) for early postmenopausal, compared with premenopausal, women were 2.1 (95% confidence interval: 1.5, 2.9). High density lipoprotein cholesterol also peaked in late peri- and early postmenopause. Results for estradiol and follicle-stimulating hormone confirmed the results based on status defined by bleeding patterns. Increases in lipids were smallest in women who were heaviest at baseline.

Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition is one strategy for increasing HDL-C. This study evaluated the lipid-altering efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy or coadministered with atorvastatin in patients with dyslipidemia. METHODS: A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia (53.8% of the study population had low HDL-C) were randomized equally to one of 10 groups: 5 groups received background statin therapy of atorvastatin 20 mg and 5 did not, and each of these was randomized to placebo, anacetrapib 10, 40, 150, and 300 mg once daily for 8 weeks. An equal proportion of patients had triglycerides >150 mg/dL in each group. RESULTS: For placebo and anacetrapib monotherapy (10, 40, 150, and 300 mg), least squares mean percent changes from baseline to week 8 for low-density lipoprotein cholesterol (LDL-C) were 2%, -16%, -27%, -40%, and -39%, respectively, and for HDL-C were 4%, 44%, 86%, 139%, and 133%, respectively (P < .001 vs placebo for all doses). Coadministration of anacetrapib with atorvastatin produced significant incremental LDL-C reductions and similar HDL-C increases versus atorvastatin monotherapy. For both anacetrapib monotherapy and coadministration with atorvastatin, the LDL-C reductions were similar in patients with baseline triglyceride levels greater than and less than or equal to the median. Anacetrapib was well tolerated, and the incidence of adverse events was similar for placebo and all active treatment groups. There were no increases in systolic or diastolic blood pressure in any treatment arm. CONCLUSIONS: Anacetrapib, as monotherapy or coadministered with atorvastatin, produced significant reductions in LDL-C and increases in HDL-C; the net result of treatment with anacetrapib + atorvastatin was approximately 70% lowering of LDL-C and more than doubling of HDL-C. Anacetrapib was generally well tolerated with no discernable effect on blood pressure.

Extended-release niacin/laropiprant: reducing niacin-induced flushing to better realize the benefit of niacin in improving cardiovascular risk factors.

Treatment with niacin effectively improves multiple lipid parameters and cardiovascular outcomes. Widespread use of niacin, however, is limited by flushing, which is mediated primarily by prostaglandin D2 (PGD2). Laropiprant is a selective PGD2 receptor 1 (DP1) antagonist that reduces objective measures of niacin-induced flushing symptoms upon initiation of therapy and with more chronic use. Results from early dosing and formulation studies have culminated in the development of a combination extended-release (ER) niacin/laropiprant tablet aimed at providing the beneficial lipid-modifying effects of niacin, while reducing niacin-induced flushing. The improvement in the tolerability of niacin with ER niacin/laropiprant allows niacin dosing to initiate directly at 1 g and rapidly advance to a 2-g target dose. ER niacin/laropiprant generally is tolerated well and represents a new treatment option for dyslipidemia that offers the potential for more patients to receive the lipid-modifying and cardiovascular benefits of niacin.

Ethnic differences in C-reactive protein concentrations.

BACKGROUND: Limited data exist regarding the ethnic differences in C-reactive protein (CRP) concentrations, an inflammatory marker associated with risk of cardiovascular disease (CVD). We hypothesized that known CVD risk factors, including anthropometric characteristics, would explain much of the observed ethnic variation in CRP. METHODS: We performed a cross-sectional analysis of 3154 women, without known CVD and not receiving hormone therapy, enrolled in the Study of Women's Health Across the Nation (SWAN), a multiethnic prospective study of pre- and perimenopausal women. RESULTS: The study population was 47.4% white, 27.7% African-American, 8.5% Hispanic, 7.7% Chinese, and 8.6% Japanese; mean age was 46.2 years. African-American women had the highest median CRP concentrations (3.2 mg/L), followed by Hispanic (2.3 mg/L), white (1.5 mg/L), Chinese (0.7 mg/L), and Japanese (0.5 mg/L) women (all pairwise P < 0.001 compared with white women). Body mass index (BMI) markedly attenuated the association between ethnicity and CRP. After adjusting for age, socioeconomic status, BMI, and other risk factors, African-American ethnicity was associated with CRP concentrations >3 mg/L (odds ratio 1.37, 95% CI 1.07-1.75), whereas Chinese and Japanese ethnicities were inversely related (0.58, 0.35-0.95, and 0.43, 0.26-0.72, respectively). CONCLUSIONS: Modifiable risk factors, particularly BMI, account for much but not all of the ethnic differences in CRP concentrations. Further study is needed of these ethnic differences and their implications for the use of CRP in CVD risk prediction.

Depressive symptoms and smoking cessation after hospitalization for cardiovascular disease.

BACKGROUND: Although smoking cessation is essential for prevention of secondary cardiovascular disease (CVD), many smokers do not stop smoking after hospitalization. Mild depressive symptoms are common during hospitalization for CVD. We hypothesized that depressive symptoms measured during hospitalization for acute CVD would predict return to smoking after discharge from the hospital. METHODS: This was a planned secondary analysis of data from a placebo-controlled, double-blind, randomized trial of bupropion hydrochloride therapy in 245 smokers hospitalized for acute CVD. All subjects received smoking counseling in the hospital and for 12 weeks after discharge. Depressive symptoms were measured during hospitalization with the Beck Depression Inventory (BDI), and smoking cessation was biochemically validated at 2-week, 12-week, and 1-year follow-up. The effect of depressive symptoms on smoking cessation was assessed using multiple logistic regression and survival analyses. RESULTS: Twenty-two percent of smokers had moderate to severe depressive symptoms (BDI >or= 16) during hospitalization. These smokers were more likely to resume smoking by 4 weeks after discharge (P= .007; incidence rate ratio, 2.40; 95% confidence interval, 1.48-3.78) than were smokers with lower BDI scores. Smokers with low BDI scores were more likely to remain abstinent than were those with high BDI scores at 3-month follow-up (37% vs 15%; adjusted odds ratio, 3.02; 95% confidence interval, 1.28-7.09) and 1-year follow-up (27% vs 10%; adjusted odds ratio, 3.77; 95% confidence interval, 1.31-10.82). We estimate that 27% of the effect of the BDI score on smoking cessation was mediated by nicotine withdrawal symptoms. CONCLUSIONS: Moderate to severe depressive symptoms during hospitalization for acute CVD are independently associated with rapid relapse to smoking after discharge and lower rates of smoking cessation at long-term follow-up. The relationship was mediated in part by the stronger nicotine withdrawal symptoms experienced by smokers with higher depressive symptoms.

Bupropion for smokers hospitalized with acute cardiovascular disease.

PURPOSE: Smoking cessation after myocardial infarction reduces cardiovascular mortality, but many smokers cannot quit despite state-of-the-art counseling intervention. Bupropion is effective for smoking cessation, but its safety and efficacy in hospitalized smokers with acute cardiovascular disease is unknown. METHODS: A five-hospital randomized double-blind placebo-controlled trial assessed the safety and efficacy of 12 weeks of sustained-release bupropion (300 mg) or placebo in 248 smokers admitted for acute cardiovascular disease, primarily myocardial infarction and unstable angina. All subjects had smoking counseling in the hospital and for 12 weeks after discharge. Cotinine-validated 7-day tobacco abstinence, cardiovascular mortality, and new cardiovascular events were assessed at 3 months (end-of-treatment) and 1 year. RESULTS: Validated tobacco abstinence rates in bupropion and placebo groups were 37.1% vs 26.8% (OR 1.61, 95% CI, 0.94-2.76; P=.08) at 3 months and 25.0% vs 21.3% (OR, 1.23, 95% CI, 0.68-2.23, P=.49) at 1 year. The adjusted odds ratio, after controlling for cigarettes per day, depression symptoms, prior bupropion use, hypertension, and length of stay, was 1.91 (95% CI, 1.06-3.40, P=.03) at 3 months and 1.51 (95% CI, 0.81-2.83) at 1 year. Bupropion and placebo groups did not differ in cardiovascular mortality at 1 year (0% vs 2%), in blood pressure at follow-up, or in cardiovascular events at end-of-treatment (16% vs 14%, incidence rate ratio [IRR]1.22 (95% CI: 0.64-2.33) or 1 year (26% vs 18%, IRR 1.56, 95% CI 0.91-2.69). CONCLUSIONS: Bupropion improved short-term but not long-term smoking cessation rates over intensive counseling and appeared to be safe in hospitalized smokers with acute cardiovascular disease.

Application of national screening criteria for blood pressure and cholesterol to perimenopausal women: prevalence of hypertension and hypercholesterolemia in the Study of Women's Health Across the Nation.

National screening guidelines for hypertension and cholesterol were applied to the multiethnic sample of perimenopausal women (N = 1349) in the Study of Women's Health Across the Nation (SWAN). To reduce low-density lipoprotein, lifestyle modification was indicated in 9.5% of patients and drug therapy in 5%. Chinese and Japanese women were least likely and African Americans were most likely to require interventions. Among all women, 27% were prehypertensive, 23% were hypertensive (blood pressure >140/90 mm Hg or treated), and 9.1% were untreated hypertensive. Untreated hypertension was lowest among Japanese and Chinese and highest among Hispanic and African-American women. Among all hypertensives, 60.5% were treated and only 58.5% of those treated were controlled. Control rates were lowest among African Americans and Hispanics. In this relatively low-risk population, a significant proportion of women with hypertension or hypercholesterolemia were either not treated, not treated adequately, or had borderline risk factors that would benefit from lifestyle interventions to prevent the need for future drug treatment.

Relation of cardiovascular risk factors in women approaching menopause to menstrual cycle characteristics and reproductive hormones in the follicular and luteal phases.

CONTEXT: Menstrual cycle characteristics may be associated with cardiovascular disease (CVD) risk. OBJECTIVE: The objective of this study was to describe the relationships between menstrual cycle characteristics and daily reproductive hormone measures with CVD risk factors in middle-aged women. DESIGN AND SETTING: Cross-sectional associations were examined between CVD risk factors and urinary LH, FSH, estrone conjugates, and pregnanediol glucuronide (Pdg) measured across one menstrual cycle or 50 d. PARTICIPANTS: Menstruating women (n = 500) who were free from diabetes or past stroke or heart attack enrolled in the Daily Hormone Study-Study of Women's Health across the Nation were studied. MAIN OUTCOME MEASURES: Body mass index (BMI), blood pressure, hemostatic, and metabolic factors were measured. RESULTS: Few differences existed in risk factors between women with evidence of luteal activity and those with no evidence of luteal activity. Associations between elevated CVD risk factors and long cycle length were reduced substantially by age and BMI adjustments. Those with lower estrone conjugate and PdG averaged across the follicular phase had higher waist circumference, triglycerides, insulin, plasminogen activator inhibitor type-1, tissue type plasminogen activator-antigen, and factor VIIc levels in age- and BMI-adjusted analyses (P < 0.05). CONCLUSIONS: In midlife menstruating women, a longer cycle length was related to CVD risk factors, in large part through their common association with BMI. More favorable levels of metabolic and hemostatic factors were associated with higher levels of follicular-phase estrogen, a pattern consistent with a more competent ovary, and higher levels of follicular-phase PdG, perhaps of adrenal origin. Metabolic and hemostatic factors may be sensitive to hormonal variation during the early perimenopausal transition.

Ethnic variation in hypertension among premenopausal and perimenopausal women: Study of Women's Health Across the Nation.

Data are sparse regarding hypertension prevalence, treatment, and control among some ethnic groups of American women. Furthermore, the effects of ethnicity on hypertension, independent of other factors that vary with ethnicity, are poorly understood. We examined the prevalence of hypertension (defined as systolic > or =140 or diastolic > or =90 mm Hg or receiving treatment), treatment, and control (to <140/<90 mm Hg) in a multiethnic study of premenopausal and perimenopausal women. Stepwise multivariable logistic regression was used to select covariates associated with hypertension. Among 3292 women, 46.9% were white, 28.3% were black, 8.7% were Hispanic, 7.6% were Chinese, and 8.5% were Japanese. Among these 5 ethnic groups, respectively, there was substantial variation in prevalence of normal blood pressure levels (<120/<80 mm Hg; 59.9%, 35.4%, 16.8%, 67.2%, and 63.7%) and hypertension (14.5%, 38.1%, 27.6%, 12.8%, and 11.0%). After multivariable adjustment, hypertension prevalence was 2 to 3x higher among black and Hispanic women but similar among Chinese and Japanese women compared with white women. Among hypertensive participants, prevalence of antihypertensive treatment was highest among blacks (58.9%) and whites (55.2%) and lowest among Chinese (34.4%). Prevalence of control to goal blood pressure levels was highest among whites (43.0%) and Japanese (38.7%) and markedly lower among Hispanic women (11.4%). Compared with whites, black and Hispanic women have significantly higher prevalence of hypertension independent of other factors, whereas Chinese and Japanese women have similar prevalence. Treatment and control rates vary considerably across ethnicities. Greater efforts must be made to improve hypertension awareness, treatment, and control in all middle-aged women, particularly those in ethnic minority groups.