Richard C. Pasternak

Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.

AHA/ACC Guidelines for Preventing Heart Attack and Death in Patients With Atherosclerotic Cardiovascular Disease: 2001 Update A Statement for Healthcare Professionals From the American Heart Association and the American College of Cardiology

Since the original publication (in 1995) of the American Heart Association (AHA) consensus statement on secondary prevention, which was endorsed by the American College of Cardiology (ACC), important evidence from clinical trials has emerged that further supports the merits of aggressive risk reduction therapies for patients with atherosclerotic cardiovascular disease. As noted in that statement, aggressive risk factor management clearly improves patient survival, reduces recurrent events and the need for interventional procedures, and improves the quality of life for these patients.nnThe compelling evidence from recent clinical trials was the impetus …

Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion.

Dilatation of infarcted segments (infarct expansion) may occur during recovery from myocardial infarction, but the fate of noninfarcted segments is uncertain. Accordingly, left ventricular geometric changes were assessed by left ventricular angiography and M mode echocardiography on admission and 2 weeks later in 30 patients with their first acute transmural myocardial infarction. All patients demonstrated chest pain, ST segment elevation with subsequent development of Q waves (15 anterior, 15 inferior), and elevation of cardiac enzymes. Sequential left ventricular angiographic and hemodynamic findings were available in these patients by virtue of their participation in a study of thrombolysis in acute myocardial infarction. By that study design, all patients treated successfully with thrombolytic therapy and demonstrating improvement of flow in an occluded coronary artery underwent repeat cardiac catheterization. At 2 weeks there was a significant decrease in left ventricular and pulmonary capillary wedge pressures (p less than .01), whereas both left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volume indexes increased (p less than .01). The increase in LVEDV correlated directly with the percentage of the ventriculographic silhouette that was akinetic or dyskinetic at the initial catheterization (r = .71, p less than .001). To assess regional changes in both infarcted and noninfarcted segments, serial endocardial perimeter lengths of both the akinetic-dyskinetic segments (infarction zone) and of the remainder of the cardiac silhouette (noninfarction zone) were measured in all patients who demonstrated at least a 20% increase in their LVEDV at 2 weeks after myocardial infarction. Notably, there was a mean increase of 13% in the endocardial perimeter length of infarcted segments and a 19% increase in the endocardial perimeter length of noninfarcted segments. Serial M mode echocardiographic studies showed no significant change in the wall thickness of noninfarcted myocardial segments. Hemodynamic changes that occurred in this subgroup of patients included significant decreases in left ventricular end-diastolic and pulmonary capillary wedge pressures (p less than .05) and significant increases in angiographic cardiac index (p less than .01) and LVESV index (p less than .01). We conclude that in patients who manifest cardiac dilatation in the early convalescent period after myocardial infarction, there is remodeling of the entire left ventricle including infarct expansion of akinetic-dyskinetic segments and volume-overload hypertrophy of noninfarcted segments.(ABSTRACT TRUNCATED AT 400 WORDS)

Guide to preventive cardiology for women

Coronary heart disease (CHD) is the single leading cause of death and a significant cause of morbidity among American women.1 Risk factors for CHD in women are well documented.2 Compelling data from epidemiological studies and randomized clinical trials show that CHD is largely preventable. Assessment and management of several risk factors for CHD are cost-effective.3 Despite these facts, there are alarming trends in the prevalence and management of risk factors in women.2 Smoking rates are declining less for women than for men. The prevalence of obesity is increasing, and ≈25% of women report no regular sustained physical activity.4 Approximately 52% of women >45 years old have elevated blood pressure, and ≈40% of women >55 years old have elevated serum cholesterol.5 The purpose of this statement is to highlight risk factor management strategies that are appropriate for women with a broad range of CHD risk. A more detailed description, including the scientific basis for these recommendations, is available in the 1997 American Heart Association scientific statement “Cardiovascular Disease in Women.”2 nnRecently, the Centers for Disease Control and Prevention National Ambulatory Medical Care Survey6 showed clinicians are missing opportunities to prevent CHD. In this study of 29 273 routine office visits, women were counseled less often than men about exercise, nutrition, and weight reduction. In the multicenter Heart and Estrogen/progestin Replacement Study (HERS),7 only 10% of women enrolled with documented CHD had baseline LDL-cholesterol levels below a National Cholesterol Education Program (NCEP) target of 100 mg/dL. A recent national survey showed that women were significantly less likely than men to enroll in cardiac rehabilitation after an acute …

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

BACKGROUNDnHigh-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.nnnMETHODSnA 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.nnnRESULTSnFor 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.nnnCONCLUSIONSnAnacetrapib, 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.

Ethnic Differences in C-Reactive Protein Concentrations

BACKGROUNDnLimited 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.nnnMETHODSnWe performed a cross-sectional analysis of 3154 women, without known CVD and not receiving hormone therapy, enrolled in the Study of Womens Health Across the Nation (SWAN), a multiethnic prospective study of pre- and perimenopausal women.nnnRESULTSnThe 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).nnnCONCLUSIONSnModifiable 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.

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 Womens 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.

Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.

Background:u2002 Improving lipids beyond low‐density lipoprotein cholesterol (LDL‐C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid‐modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D2 (PGD2). Laropiprant (LRPT), a PGD2 receptor (DP1) antagonist that reduces niacin‐induced flushing has been combined with extended‐release niacin (ERN) into a fixed‐dose tablet.

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 patients 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.

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.