Elizabeth Barrett-Connor, MD
University of California, San Diego,
   School of Medicine

Peter Ganz, MD
Harvard Medical School
Brigham and Women's Hospital

Scott M. Grundy, MD, PhD
University of Texas Southwestern
   Medical Center at Dallas

Steven M. Haffner, MD
University of Texas Health Science Center

Donald B. Hunninghake, MD
University of Minnesota Medical School

Ronald M. Krauss, MD
Lawrence Berkeley National Laboratory
University of California, Berkeley

John C. LaRosa, MD
SUNY Downstate Medical Center

Peter Libby, MD
Harvard Medical School
Brigham and Women's Hospital

Harry L. Metcalf, MD
SUNY/Buffalo School of Medicine and
   Biomedical Sciences

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Supported by an unrestricted educational grant from Pfizer Inc

Thomas A. Pearson, MD, MPH, PhD
Albert D. Kaiser Professor and Chair
University of Rochester School of Medicine
Rochester, New York

CITATIONS: Ford ES, Mokdad AH, Giles WH, Mensah GA. Serum total cholesterol concentrations and awareness, treatment, and control of hypercholesterolemia among US adults: findings from the National Health and Nutrition Examination Survey, 1999 to 2000. Circulation. 2003;107:2185-2189. • Arnett DK, McGovern PG, Jacobs DR, et al. Fifteen-year trends in cardiovascular risk factors (1980-1982 through 1995-1997): the Minnesota Heart Survey. Am J Epidemiol. 2002;156:929-935.

COMMENTARY: Is the National Cholesterol Education Program (NCEP) making progress?
    In the past 12 months, two large population-based studies have examined serum cholesterol levels in the United States over 10 years or more. The study by Ford et al uses data from the National Health and Nutrition Examination Survey (NHANES) of 1999-2000 and compares results with data from NHANES III, performed 1988-1994. These surveys target statistically representative samples of the US population. Serum cholesterol levels were measured in standardized fashions in both time periods. The study by Arnett et al analyzed data from the four Minnesota Heart Surveys from 1980 to 1997, again drawing a sample representative of the population and using standardized measures of serum cholesterol. These two studies provide our best picture of cholesterol levels in the US during the 1990s, ie, since the inception of the NCEP in late 1987.
    The two studies agree in their observations that serum cholesterol levels have not changed in the 1990s. NHANES 1999-2000 shows no significant change in serum total cholesterol levels from NHANES III, with some reductions in older age groups but trends of increasing cholesterol levels in younger persons. The Minnesota Heart Surveys show similar trends, with reductions in total cholesterol levels in the 1980s but none since 1990. During this time period, use of lipid-lowering drug therapy doubled or tripled in both study populations.
    Both papers provide insights as to the reasons for lack of further declines. The NHANES data from 1999-2000 demonstrate that, of 100 adults with actual hypercholesterolemia, only 40% are detected and aware, only 14% are treated, and only 7% have cholesterol levels <200 mg/dL. Thus, gaps between care recommended by the NCEP and that actually received by the typical hypercholesterolemic American adult are large for screening, diagnosis, and treatment. The Minnesota Heart Survey documents reductions in saturated fat and Keys Scores (a measure of cholesterol-raising effects of diet), but these benefits appear more than neutralized by an increase in calorie ingestion, reduction in calorie expenditure, and increases in body weight and body mass index.
    These two large, reputable studies suggest little progress in the 1990s toward reduction in cholesterol levels in the United States, despite use of cholesterol drugs increasing to 6.8% of adult women and 9.0% of adult men by 2000. The lag in diagnosis, treatment, and control suggests that the NCEP may need more resources to influence physician and patient behaviors. The huge deficiency in screening and the detrimental effects of obesity appear to have effectively counter-balanced any reductions due to dietary change or cholesterol-lowering drugs. Taken together, the results of these studies question whether the current Adult Treatment Panel (ATP III) approach is sufficient to enable populationwide cholesterol levels to decline as they did between 1970 and 1990. Serious consideration needs to be given to populationwide, not clinical, approaches such as those proposed by the NCEP Population Panel. Given the disappointing trends documented by these two studies, a reconvention of the Population Panel is needed to consider additional public health strategies for control of hypercholesterolemia in the United States.

W. Virgil Brown, MD
Charles Howard Candler Professor of Medicine
Emory University School of Medicine
Chief of Medicine, Atlanta VAMC
Atlanta, Georgia

CITATION: ASCOT Investigators Group. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentration in ASCOT-LLA: a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158.

COMMENTARY: Primary-care providers should be aware of the several implications of the recent report of the ASCOT-LLA [Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm] study. This trial is important, for it provides confirmation that the most commonly used drug to reduce LDL-C, atorvastatin, can prevent acute coronary syndromes and stroke. Many had made that assumption based on several smaller trials, such as AVERT [Atorvastatin Versus Revascularization Treatment] and MIRACL [Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering]. However, until ASCOT, no long-term trial with a broad range of patients had provided convincing statistical evidence that the incidence of myocardial infarction (MI) and coronary artery disease (CAD) death could be reduced. The impact of treatment with atorvastatin (10 mg/day) in this population of over 10,000 patients was dramatic. The plan was for a trial duration of 5 years, but the Data and Safety Monitoring Committee halted the study after only 3.3 years because the primary endpoint of MI and CAD death was sufficiently different from the placebo control—enough so that the stopping rules were surpassed and continuation was considered unethical. The analysis of the data accumulated at that point revealed a 36% reduction in MI and CAD death (P<0.0005).
    It is important to recognize that, although ASCOT was conducted in a population without a history of CAD and with total cholesterol <250 mg/dL, it was a very high-risk population of patients with high blood pressure and at least two other risk factors for MI and CAD death. The results are consistent with a fundamental idea underlying the approach of the National Cholesterol Education Program guidelines; that is, persons should be treated with more urgency and more aggressively in proportion to their cumulative risk.

Robert Chilton, DO
Associate Professor of Medicine
University of Texas Health Science Center
San Antonio, Texas

CITATION: Lee C, Chawla A, Urbiztondo N, et al. Transcriptional repression of atherogenic inflammation: modulation by PPARδ. Science. 2003;302:453-457.

COMMENTARY: Are PPARs the ultimate therapeutic target in vascular health?
    Inflammation and oxidative stress are at the forefront of atherosclerosis. Recently, Lee and coworkers have identified new molecular targets that affect lipid homeostasis, inflammation, and the development of atherosclerosis. This new therapeutic target for atherosclerosis is part of the family of nuclear receptors called PPARs (peroxisome proliferator-activated receptors). For the clinician, the PPAR-agonist class of drugs is normally used for the treatment of patients with type 2 diabetes; this research paper, however, goes far beyond just glucose control, suggesting that they may confer anti-inflammatory and antiatherosclerotic benefits. From the authors’ research, it would appear that PPARδ controls an inflammatory switch. PPARδ and its ligands may be excellent clinical therapeutic targets to attenuate inflammation and slow the progression of atherosclerosis.
    The PPAR agonists may be the next new treatment class of drugs for patients with cardiovascular disease, with possible plaque-stabilizing, anti-inflammatory, and antiatherosclerotic properties. Clearly, much more research is needed, but one needs only to look at the history of statins to appreciate the possibilities of PPAR agonists for cardiovascular disease.

Ronald B. Goldberg, MD
Associate Director
Diabetes Research Institute
Miami, Florida

CITATION: Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005-2016.

COMMENTARY: In the multicenter, United Kingdom-based Heart Protection Study (HPS), the largest clinical trial of its kind, 5,963 adults aged 40 to 80 years were randomized either to simvastatin 40 mg/day or placebo. All were known to have diabetes, with and without cardiovascular disease (CVD), and total cholesterol and LDL-C levels not considered by their general practitioners to warrant statin therapy. The objective was to determine whether major CVD events were reduced by simvastatin treatment over a 5-year period.
    The findings were quite clearcut. Among the 2,912 diabetic subjects without evident CVD at entry and with average LDL-C levels, simvastatin treatment reduced the first major cardiovascular event by 33% (P<0.001), whereas in diabetic subjects with CVD, there was a significant 18% reduction in first events (P<0.002). The apparent difference in effect in these two diabetic groups may simply reflect the play of chance in these relatively small subgroups. More importantly, the rate of first events in the placebo-treated group without CVD was 13% over 5 years, which strongly supports the contention that diabetic subjects (at least those with a mean age of 62 years in the HPS) without CVD should be considered to have a National Cholesterol Education Program (NCEP) CHD risk-equivalent category (>20% event rate/10 years). For diabetic subjects with CVD, the placebo group event rate for a first event in the study was 36% over 5 years, emphasizing the seriousness of established CVD disease in diabetic subjects. Simvastatin treatment significantly reduced (by about one fourth) major coronary events, ischemic stroke, revascularizations, peripheral vascular events, and recurrent events in those having their first CVD event during the study. In a previous publication, similar results were observed in the HPS nondiabetic cohort with CVD.
    A second key observation in this HPS report was the finding that the relative benefit of statin therapy in those with diabetes whose LDL-C level was <116 mg/dL at entry was similar to that obtained in individuals with baseline LDL-C values >116 mg/dL (27% reduction vs 20% in placebo-group event rates; P<0.001). Although this could not be further separated for those with or without CVD, it strongly suggests that, in diabetic subjects, statins provide benefit at LDL-C levels less than the current NCEP recommendation of >130 mg/dL. These findings led the investigators to conclude that “statin therapy should now be considered routinely for all diabetic subjects at sufficiently high risk of (such) major vascular events, irrespective of their initial cholesterol concentrations.” What, then, constitutes “sufficiently high risk for major vascular events”? In subgroup analyses, the benefit derived from statin therapy was significant irrespective of age, sex, body mass index, diabetes duration, serum creatinine, hemoglobin A_1c, TG or HDL-C levels, or the presence or absence of hypertension. Thus, other than the restriction of the study’s lower age limit of 40 years, the HPS results suggest a strong likelihood that most diabetic subjects will benefit from statin therapy. The important questions of how low to go in the treatment of LDL-C and what the role of fibrates should be if most subjects are to be treated with statins remain unanswered for now and will continue to challenge us therapeutically.
    However, the most important task we now face is to ensure that statin therapy constitutes a central feature in the management of our own patients with diabetes.

Daniel J. Rader, MD
Director, Preventive Cardiology and Lipid Clinic
Department of Medicine and Center for
    Experimental Therapeutics
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania

CITATION: Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292-2300.

COMMENTARY: Plasma levels of HDL-C and its major protein apolipoprotein A-I (apoA-I) are consistently inversely associated with coronary heart disease (CHD) risk in observational studies. Also, studies in animals have established that apoA-I can substantially slow the progression and even induce regression of preexisting atherosclerosis. However, data in humans showing that therapies targeting HDL-C can reduce atherosclerosis have been lacking.
    A recent study by Nissen and colleagues involving the infusion of apoA-I Milano can be viewed as the first study in humans supporting the concept of targeting HDL-C to induce regression of atherosclerosis. ApoA-I Milano is a mutant form of apoA-I, the major HDL-C protein found in a small number of individuals in a town in northern Italy. Because of promising studies in animals, apoA-I Milano is being developed as a therapeutic approach to atherosclerosis. The investigators recruited patients who were hospitalized with acute coronary syndromes and who required coronary angiography clinically. After a baseline angiogram that included intravascular ultrasound (IVUS) of a segment within a “target vessel” that did not undergo revascularization, study participants received weekly infusions of recombinant apoA-I Milano complexed with phospholipids for 5 weeks. At week 6, a repeat coronary IVUS study was performed to measure changes in the amount of atherosclerosis within the target segment.
    The results of this study are surprising to even the most optimistic supporters of the concept of targeting HDL-C as a therapy for atherosclerosis. Patients who received the five infusions of apoA-I Milano experienced statistically significant regression in coronary atheroma volume in the target segment compared with baseline measurements. A smaller placebo group that received only saline infusions had no significant change in atheroma volume.
    Although exciting, there are some limitations to the interpretation of these study results. The study was quite small and was not designed or powered for direct comparison between the two groups, which also differed at baseline in the extent of atheroma volume. Two different doses of the apoA-I Milano infusion were used, but no evidence of a dose-response relationship was seen. Therefore, the results must be replicated in a larger study. Finally, we have no data as to whether changes in coronary atheroma burden as measured by IVUS are a reliable surrogate for clinical benefit, and outcome studies with apoA-I Milano will need to be performed. Nevertheless, this study provides the best example to date that directly targeting HDL-C can have an impact on atherosclerosis in humans.
    An interesting aspect of this study is the rapid regression induced by apoA-I Milano infusions. This raises the intriguing question of whether some day patients with acute coronary syndromes may receive “acute induction therapy” targeting HDL-C for rapid regression and stabilization of lesions. Ultimately, the study’s importance is to generate proof of principle that targeting HDL-C can rapidly regress atherosclerosis, ushering in a new era of focus on HDL-C–based therapies.

Richard C. Pasternak, MD
Associate Professor of Medicine
Harvard Medical School
Director of Preventive Cardiology
     and Cardiac Rehabilitation
Massachusetts General Hospital
Boston, Massachusetts

CITATIONS: Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419-1423. • Rodgers A. A cure for cardiovascular disease? Combination treatment has enormous potential, especially in developing countries. BMJ. 2003;326:1407-1408. • Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systemic review and meta-analysis. BMJ. 2003;326:1423-1427. • Law MR, Wald NJ, Morris JK, Jordon RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326:1427-1434.

COMMENTARY: In three provocative papers, and an accompanying editorial, in the June 28, 2003, issue of the British Medical Journal, the prevention world was introduced to what some have termed a “radical concept.” The idea has already generated considerable controversy and interest. The new intervention, described as potentially having “a greater impact on the prevention of disease in the Western World than any other known intervention,” is not new magic, but rather a new strategy to deliver well-known interventions, a strategy termed by the senior authors as the “Polypill.” These authors, Wald and Law, are thoughtful epidemiologists who have conducted critical risk-factor analyses for well over a decade. The key paper introduces the strategy of the Polypill and explains how this intervention could reduce cardiovascular disease by more than 80%. In the two accompanying manuscripts, the authors perform meta-analyses of randomized controlled trials of statin and blood pressure–lowering therapies, key components of the Polypill. Wald and Law suggest that the Polypill should comprise six components: a statin, a thiazide diuretic, an ACE inhibitor, a calcium channel blocker, folic acid, and low-dose aspirin. The authors contend that, based on a careful review of meta-analyses (including many of their own), use of this combination would reduce ischemic heart disease events by 88% and stroke by 80%. They suggest that the pill would benefit all people with known cardiovascular disease, as well as everyone over the age of 55 years.
    Critics have immediately responded by suggesting that the incidence of side effects would be unacceptable and that many people would be treated unnecessarily. Anticipating criticism, Wald and Law have also analyzed the cumulative adverse event rate that might be anticipated. From this, they developed a model in which they predict expected benefits for 100 men and 100 women treated with the Polypill. They calculate that roughly 35 individuals will benefit for an average net of approximately 12 years of life gained per patient treated.
    Regardless of the eventual fate of the Polypill, the discussion of these issues is important and provocative. By 2020, the World Health Organization estimates that ischemic heart disease will be the number one cause of death and disability worldwide. Given this enormous burden of disease and the known difficulties with long-term adherence—particularly to complex and multiple strategies—and given the realities of difficult lifestyle changes, the notion of lowering risk by 80% by taking a daily pill deserves thoughtful consideration by practitioners and by health-policy specialists. The discussion should also serve to remind busy practitioners that existing therapies (whether bundled into a single pill or not) have the capacity to dramatically alter the horizon of cardiovascular disease in our population.
    In a separate comment, the editor of BMJ added, “I suggest, gentle (or even angry) reader, that you keep this issue of BMJ. It may well become a collector’s item. It’s perhaps more than 50 years since we’ve published something as important as the cluster of papers from Nick Wald, Malcolm Law, and others.”

Daniel Eisenberg, MD, FACC
Director, Cardiology
Providence St Joseph Hospital Burbank
Associate Clinical Professor of Medicine
The Keck School of Medicine of the
    University of Southern California
Los Angeles, California

CITATION: Muller I, Besta F, Schulz C, et al. Effects of statins on platelet inhibition by a high loading dose of clopidogrel. Circulation. 2003;108:2195-2197.

COMMENTARY: This is a timely study that addresses a very important clinical topic relating to the hundreds of thousands of patients treated with a percutaneous coronary intervention (PCI) annually, plus concomitant antiplatelet and statin therapies. The authors studied the effects of multiple statins on the antiplatelet activity of clopidogrel in 77 patients with stable coronary disease. This study was undertaken because of recent data that reached differing conclusions as to whether statins may have deleterious effects on platelet inhibition conferred by clopidogrel.
    Platelet aggregation studies were performed with atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin (each 20 mg), cerivastatin (0.3 mg), or placebo, plus a high loading dose of clopidogrel (600 mg). No decrement in platelet-activating effects was found in any of the statin/clopidogrel groups.
    Therefore, it seems wise to preload patients with 600 mg clopidogrel during a PCI and continue the use of statins in these high-risk patients.