- Email: [email protected]
The Year in Atherothrombosis
Journal of the American College of Cardiology © 2008 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 51, No. 9, 2008 ISSN 0735-1097/08/$34.00 doi:10.1016/j.jacc.2007.12.018
YEAR IN CARDIOLOGY SERIES
The Year in Atherothrombosis Javier Sanz, MD, Pedro R. Moreno, MD, FACC, Valentin Fuster, MD, PHD, FACC New York, New York The present review aims to summarize relevant studies published during the last year in the field of atherothrombosis. A special emphasis was placed on the promotion of cardiovascular health worldwide, as well as on the need for a progressive shift from the treatment of advanced disease to early detection and enhanced prevention. Epidemiology and Public Health Impact Important information on the magnitude of the burden of cardiovascular disease (CVD) became available in 2007. During the last 2 decades, coronary heart disease (CHD) age-specific death rates fell by ⬎40% in high-income countries (1,2). Prolonged survival has translated into growing disease prevalence and number of hospitalizations, with much smaller reductions in absolute mortality and staggering financial burden: the estimated annual cost of CVD in the U.S. is $431 billion (1,3). The 1-year incidence of death, myocardial infarction (MI), stroke, or hospitalization for an atherothrombotic event is 14% for patients with established atherosclerotic disease, and 5% for patients with multiple (⬎2) risk factors, according to an international registry (4). With continuing increase in expenditure and progressive aging of the population, the present healthcare system appears unsustainable in the long run (5). The importance of considering CVD a global health priority was emphasized: CVD is the main killer also in low- and middleincome countries, and causes 3 times more deaths than the most lethal infectious diseases combined. In developing countries, CVD affects younger people of working age and has additional economic impact (6). Up to 50% of the reduction in age-adjusted mortality from CHD can be attributed to the application of evidencebased therapies rather than to effective prevention (1,2,7). Although the remaining improvement in survival can be explained by reductions in some risk factors, obesity and diabetes markedly increased, as well as the burden of CVD attributable to diabetes (2,8). Of major concern, risk profile worsened in children and adolescents: hypertension, obesity, diabetes, and physical inactivity escalated, whereas cholesterol levels and tobacco use remained unchanged (9). In From The Zena and Michael A. Wiener Cardiovascular Institute/Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, New York. Manuscript received November 12, 2007; accepted December 13, 2007.
developing regions, the prevalence of traditional risk factors is on the rise in both adults and the young (6). According to a survey in ⬎168,000 primary care patients in 63 countries worldwide, ⬎60% of men and ⬎50% of women are either overweight or obese in all regions except southern and eastern Asia (10). Approximately 25% of the world population smokes, with two-thirds living in 15 low- and middle-income countries (11). Tobacco smoke exposure was shown to cause dose-dependent endothelial dysfunction in children (12). Smoking and obesity/inactivity have become the 2 leading modifiable causes of premature death (13). Early Detection and Risk Assessment Traditional risk factors. Traditional risk factors continued to be the cornerstone of prevention and risk stratification. A report from NHANES (National Health and Nutrition Examination Survey) estimated that the percentages of adult Americans falling into the low, moderate, moderateto-high, high, and very-high risk categories are 61.1%, 17.2%, 5.4%, 10.6%, and 5.7%, respectively (Fig. 1) (14). These findings suggest that the “intermediate-risk” group may be smaller than previously thought. The European Society of Cardiology updated region-specific charts for predicting the 10-year risk of a first fatal atherosclerotic event based on age, gender, smoking habit, systolic blood pressure, and total cholesterol (15). In an attempt to improve primary prevention worldwide, the World Health Organization proposed the use of similar simplified region-specific charts that also consider the presence of diabetes (16). A number of studies evaluated the roles of lipids in cardiovascular risk. The relationship between age, lipid profile, and incident fatal MI was evaluated in ⬎128,000 subjects followed for a mean of 10.3 years. Most of the excess risk associated with age could be attributed to long-term exposure to a proatherogenic lipid environment, thus suggesting that it is potentially modifiable (17). Independent, long-term associations with MI, CHD, and death were also described for nonfasting concentrations of serum triglycerides in both men and women (18). Several studies addressed the relationship between obesity and CVD. The waist-to-hip ratio was independently associated with the presence of coronary calcium by computed
Sanz et al. Year in Atherothrombosis
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
Figure 1
Distribution of CV Risk and LDL Levels in American Adults
Absolute numbers of individuals (in millions) for each National Cholesterol Education Program Adult Treatment Panel III risk category and level of low-density lipoprotein cholesterol (LDL-C) are shown. Those meeting the recommended LDL-C target levels are highlighted in green, those requiring therapeutic changes are indicated in red, and those in whom therapeutic changes could be appropriate are shown in yellow. The majority of the population falls into the low-risk category; however, it is evident that most individuals with the highest risk do not meet the desired LDL-C goal. CV ⫽ cardiovascular. Reprinted, with permission, from Keevil et al. (14).
tomography (CT) and of aortic plaque by magnetic resonance imaging (MRI) (19). The contribution of subclinical CVD to future events in obese individuals was highlighted in the Framingham Offspring study (20). Both abdominal visceral and subcutaneous adiposity correlated with markers of inflammation or oxidative stress (21), reinforcing the proatherogenic state associated with obesity (Fig. 2) (22). Regarding glucose metabolism, a high dietary glycemic load was independently associated with increased risk of CHD in women (23). Elevated fasting glucose independently predicted heightened CVD mortality in 10,428 Australian subjects (24), but this risk was markedly mitigated in the absence of the metabolic syndrome in another investigation including ⬎30,000 Chinese individuals (25). A metaanalysis of 37 longitudinal studies and ⬎173,000 patients reported a relative risk of 1.78 for cardiovascular events and death associated with the metabolic syndrome, which remained significant even after adjustment for its individual components (26). Serum biomarkers. Among the many reports published in 2007 evaluating the diagnostic and prognostic significance of numerous biomarkers, several studies deserve special consideration. A novel algorithm from the Women’s Health study including C-reactive protein (CRP) and, in diabetic patients, hemoglobin A1C was developed and validated. It resulted in reclassification of risk category in 30% to 45% of intermediate-risk women, with superior predictive ability than the NCEP ATP-III (National Cholesterol Education Program Adult Treatment Panel III) model (27). Arguing
945
against routine CRP measurement, NHANES investigators estimated that such approach would lead to modification of the target low-density lipoprotein (LDL) cholesterol only in 3.1% of the U.S. adults (28). In elderly participants of the Cardiovascular Health study without manifest CVD, increased levels of CRP were associated with impaired prognosis only in patients with subclinical atherosclerosis as determined by the carotid intima-media thickness (CIMT) (29). Data from the same study suggested that polymorphisms of the CRP gene contribute significantly to both plasmatic concentrations and cardiovascular risk, but not to CIMT (30). The strong prognostic implications of increased levels of N-terminal pro-brain natriuretic peptide (BNP) were highlighted in ⬎20,000 high-risk individuals from the Heart Protection study. After an average follow-up of 5 years, elevated N-terminal pro-BNP concentrations indicated markedly increased risk of not only heart failure but also occlusive atherothrombotic events (Fig. 3) (31). Comparable independent predictive ability, superior to CRP, was confirmed in a population-based study with a median follow-up of 9.4 years (32). In participants of the Framingham Offspring study in whom multiple markers of inflammation, neurohormonal activity, and endothelial dysfunction were quantified, increased levels of aldosterone and plasminogen activator inhibitor-1 were independent predictors of incident metabolic syndrome (33). Additionally, a preliminary study demonstrated correlations of plasma levels of beta2-microglobulin with the ankle-brachial index and functional capacity, and suggested a potential role specifically for the diagnosis of peripheral arterial disease (34).
Figure 2
Adipocyte Abnormalities in Obesity and the Proatherogenic Role of Adiposity
Progressive weight gain leads to adipocyte enlargement and a pro-inflammatory state with increased macrophage activation, secretion of chemokines and cytokines, and endothelial damage. ER ⫽ endoplasmic reticulum; IKK ⫽ IkappaB kinase; IL ⫽ interleukin; JNK ⫽ c-Jun N-terminal kinase; MCP ⫽ monocyte chemoattractant protein; SAA ⫽ serum amyloid A; TLR ⫽ toll-like receptor; TNF ⫽ tumor necrosis factor. Reprinted, with permission, from Gustafson et al. (22).
946
Figure 3
Sanz et al. Year in Atherothrombosis
BNP and CV Risk
Multivariate-adjusted relative risks of various cardiovascular (CV) events according to baseline levels of N-terminal (N) pro-brain natriuretic peptide (BNP). CI ⫽ confidence interval. Modified, with permission, from Emberson et al. (31).
Two studies questioned the prognostic value of individual biomarkers in the general population and suggested some, although modest, additive predictive ability of multimarker approaches over conventional risk stratification. Ten biomarkers were measured in 3,209 patients followed for a median of 7.4 years. The adjusted hazard ratio of death was 4.08 for the top versus the 2 lower quintiles of a multimarker score containing BNP, homocysteine, CRP, renin, and urinary albumin-to-creatinine ratio; the hazard ratio of major cardiovascular events was 1.84 for a score containing BNP and urinary albumin-to-creatinine ratio (35). In a second investigation the ankle-brachial index and 17 biomarkers were quantified in 1,592 patients followed for a mean of 17 years. A score including interleukin-6, intercellular adhesion molecule-1, lipoprotein(a), and tissue plasminogen activator provided some added value for the prediction of major cardiovascular events (36). Circulating endothelial progenitor cells and genetic markers. There is increasing evidence of the crucial role of endothelial progenitor cells in the repair of chronic endothelial injury secondary to cardiovascular risk factors. Both in apparently healthy individuals and in those with CVD there is an inverse correlation between the number and functional activity of endothelial progenitor cells and risk profile, indicating a delicate balance between regenerative capacity and development of disease (37). Enhancing the number and function of circulating progenitor cells is, therefore, an attractive therapeutic target, and promising
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
preliminary results with peroxisome proliferator-activated receptor-gamma agonists (glitazones) were reported (38). Homozygosity for the haptoglobin 2 gene was associated with down-regulation of the hemoglobin scavenger receptor in diabetic patients, suggesting that inability to clear toxicfree hemoglobin from intraplaque hemorrhage may be an important contributor to diabetic risk (39). In an attempt to validate previously described genetic risk factors for CVD, one investigation tested 85 variants of 70 genes in 811 patients with acute coronary syndromes and 650 control subjects. Only one variant in the beta-fibrinogen gene was marginally different between the groups (40). The inability to replicate prior associations in different populations highlighted the complexity of the interactions between multiple genetic and environmental factors, and suggests that extensive research will be necessary before the application of genetic profiling in clinical practice (41). Identification of meaningful variants will require powerful genotyping tools and validation in different populations. One such study performing genome-wide analysis compared ⬎500,000 single-nucleotide polymorphisms in 2 independent populations of patients with CHD and control subjects. Of the 7 loci that were identified as high-likelihood candidates, the strongest association was noted for a region of chromosome 9 that encodes genes involved in cell cycle regulation (42). Similar multipopulation genome-wide association studies allowed for the identification of at least 10 loci linked to type 2 diabetes, each exerting a modest effect on risk (Fig. 4) (43). Detection of subclinical disease and imaging. In apparently healthy individuals, the number of imaging tests revealing extensive atherosclerosis correlated with the Framingham score. However, there were frequent discrepancies between estimated risk and disease burden (Fig. 5) and different modalities agreed poorly with one another, highlighting the challenge of inferring information of one vascular bed from the status of another (44). Several studies addressed the prognostic implications of detecting subclinical disease in the general population. A multicenter trial randomized ⬎67,000 men of age 65 to 74 years to receive or not an invitation for ultrasonographic screening of abdominal aneurysm. After a mean follow-up of 7.1 years, aneurysm-related mortality was halved in the group invited for screening, an approach that additionally proved highly cost-effective (45). According to a meta-analysis of 8 studies enrolling ⬎31,000 individuals, the age- and genderadjusted hazard ratios of 0.1 mm increment in common CIMT were 1.15 and 1.18, respectively, for incident MI and stroke (46). The presence of occlusive and sub-occlusive peripheral arterial disease independently predicted MI and death in 1,325 individuals in whom the ankle-brachial index and carotid and femoral plaques by ultrasound were evaluated (47). Additionally, in 117 patients with prior stroke or transient ischemic attack and serial transesophageal echocardiograms, progression of aortic atheroma over 12 months was associated with an almost 6-fold increase in risk of
Sanz et al. Year in Atherothrombosis
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
Figure 4
Genetic Risk of T2D
The risk of type 2 diabetes (T2D) is estimated from a logistic regression model containing 10 susceptibility genetic variants. The x axis contains 20 equal intervals of predicted T2D risk derived from the model. The y axis shows the number (with 95% confidence limits) of T2D cases within each predicted risk interval. The horizontal dashed line indicates the sample prevalence of T2D. There is a 4-fold increase in risk of T2D (from 5% to 20%) from the lowest to the highest predicted risk categories. Modified, with permission, from Scott et al. (43). Reprinted with permission from AAAS.
subsequent cardiovascular events during a median follow-up of 1.7 years (48). The field of cardiac CT was particularly active. A new expert consensus document emphasized the incremental predictive value of calcium scoring over conventional risk factors for the occurrence of cardiovascular death or MI in asymptomatic individuals, particular those at intermediate
Figure 5
947
risk (49). This prognostic ability was reiterated in the largest series available so far (⬎25,000 patients followed for 6.8 ⫾ 3 years), which showed markedly reduced adjusted survival with increasing calcium scores (50), a risk that may be modulated by the presence of concomitant ischemia (51). Family history was shown to contribute to both development and progression of coronary calcification (52). Conversely, the influence of environmental factors was highlighted by the positive association between the calcium score and air pollution (53). Regarding contrast-enhanced coronary CT angiography, a study of 254 patients with chest pain suggested that CT is useful in subjects with low or intermediate pre-test probability, in whom a normal scan reliably rules out disease and a positive result should prompt additional testing (54). Importantly, CT was able to detect atherosclerosis, including calcified and non-calcified nonstenotic plaques, in ⬎50% of the segments considered normal by invasive catheterization (55). Computed tomography is more accurate for the evaluation of plaques in the proximal coronary segments, the most common location for thin-cap fibroatheromas and plaque ruptures as confirmed in a recent autopsy series (56). The prognostic value of CT coronary angiography was highlighted in a retrospective study of 1,127 symptomatic individuals. Besides stenosis severity and proximal disease location, the presence of ⬎5 segments with any detectable plaque was identified as an independent predictor of all-cause mortality in multivariate analysis. Survival in the absence of plaque in the left main or left anterior descending arteries surpassed 97% after an average follow-up of 15 months (57). Black-blood MRI for noninvasive plaque quantification in the coronary arteries and the aorta was employed in another investigation of type 1 diabetes mellitus. Aortic plaque extent was similar in patients with or without nephropathy, but the former had significantly increased coronary disease burden (Fig. 6), which additionally correlated with diabetes duration and total cholesterol level (58).
Distribution of Atherosclerotic Burden According to Baseline Risk
Proportions of male (A) or female (B) subjects with high atherosclerotic burden (defined as value ⬎80th percentile) in 0, 1, 2, 3, or 4 tests for the presence of subclinical disease: carotid intima-media thickness, magnetic resonance imaging-derived aortic plaque burden, aortic calcium score, and coronary calcium score. Patients are grouped according to their Framingham risk score. Modified, with permission, from Kathiresan et al. (44).
948
Figure 6
Sanz et al. Year in Atherothrombosis
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
MRI-Derived Coronary Plaque Burden
Bright-blood (A and C) and black-blood (B and D) magnetic resonance imaging (MRI) of the right coronary artery (RCA) in a patient with type 1 diabetes and normoalbuminuria (top) and a second patient with diabetic nephropathy (bottom). Both patients have a patent RCA lumen; however, the thickness of the vessel wall is markedly increased in the patient with nephropathy (D, black arrows) in comparison with the patient with normoalbuminuria (B, white arrows). Reproduced, with permission, from Kim et al. (58).
The degree of vascular inflammation assessed with combined CT and 18F-fluorodeoxyglucose positron emission tomography was significantly correlated with the number of components of the metabolic syndrome (59). Another investigation reported excellent interobserver, intraobserver, and interscan reproducibility of this technique (Fig. 7), suggesting a potential role for serial testing (60). In this regard, reductions of vessel wall inflammation after statin therapy could be demonstrated (61). Using intravascular ultrasound (IVUS), it was shown that the progression/ regression in atheroma volume in response to interventions is inversely correlated to the amount of calcification, suggesting that calcified plaques are more resistant to change (62). Optical coherence tomography, an alternative invasive modality with superb spatial resolution, demonstrated superior ability than IVUS or coronary angiography for the detection of plaque rupture/erosion or intracoronary thrombus in patients with acute MI (63). In the field of molecular imaging, successful detection of plaque inflammation with MRI was possible with gadolinium-loaded micelles coupled with antibodies against the macrophage scavenger receptor (64). An alternative approach used CT and a novel iodinated nanoparticulate contrast that is selectively taken up by macrophages to
successfully detect experimental aortic atherosclerosis (Fig. 8) (65). Vascular inflammation in various stages of atherosclerosis could be depicted using ultrasound and microbubbles targeted to vascular cell adhesion molecule-1 in mice (66). In addition, an intraoperative near-infrared fluorescence imaging system and the injection of platelets labeled with a novel fluorophore allowed for the detection of occlusive and nonocclusive thrombi in porcine carotid, femoral, and coronary arteries in vivo (67). Therapy Risk factor management and importance of medical therapy. Reinforcing the relevance of early identification of risk factors, the American Heart Association released recommendations for primary prevention in children and adolescents (9). Dietary counseling starting at infancy and maintained throughout childhood resulted in maintained decreases in total and LDL cholesterol until at least 14 years of age (68). Approximately 34% of American adults have LDL cholesterol levels above the recommended goal, and the number is ⬃75% in those with the highest risk. Moreover, in almost 50%, lower LDL concentrations would be desirable (Fig. 1) (14). Moderate-to-high levels of
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
Figure 7
Sanz et al. Year in Atherothrombosis
949
Vascular Inflammation Demonstrated With PET/CT
Sagittal images of the chest obtained with computed tomography (CT) (left), positron emission tomography (PET) (middle), and the corresponding fused images (PET/CT) (right). The top row shows the baseline scan and the bottom row a follow-up study performed 2 weeks later. Reproducible uptake of 18F-fluorodeoxyglucose in the aortic arch (arrows) can be noted in both scans. A ⫽ anterior; P ⫽ posterior. Reproduced, with permission, from Rudd et al. (60).
physical activity in daily tasks were associated with decreases in coronary events across the spectrum of baseline cardiovascular risk (69). In addition, it was estimated that a 20% decrease in the number of world smokers by 2020 could prevent 100 million premature deaths (11). One of the highlights of 2007 was the publication of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial. Of ⬎35,000 potential candidates, 2,287 patients with stable coronary disease, objective mild/moderate ischemia, and proven severe coronary stenoses were randomized to optimized medical therapy with or without percutaneous intervention (using mainly bare-metal stents). Of note, 58% of the patients had class II/III angina and 69% multivessel disease, including significant stenosis of the proximal left anterior descending artery in ⬃30%. After a median follow-up of 4.6 years, there were no significant differences between the 2 groups in rates of death, MI, stroke, or their combination (Table 1). Patients initially assigned to percutaneous intervention had lower rates of subsequent revascularization and angina, although symptoms decreased significantly in both groups (70). The results of this trial did not come without criticism (71), but overall reinforced the importance of aggressive medical management. Comparable findings came from MASS (Medicine, Angioplasty, or Surgery Study) II, which reported similar 5-year mortality for percutaneous intervention, coronary bypass surgery, or medical therapy as the treatment of stable patients with multivessel coronary disease and preserved ejection fraction, although revascular-
ization provided better symptomatic control (72). Additionally, adherence to therapies of proven benefit was independently associated with improved post-MI survival (73). However, the results of the third EUROASPIRE (European Action on Secondary Prevention through Intervention to Reduce Events-III) survey demonstrated that large proportions of patients with known CHD remain undertreated (74). Lipid therapy. A long-term follow-up of 5,778 men without previous MI enrolled in WOSCOPS (West of Scotland Coronary Prevention Study), which compared pravastatin versus placebo for 5 years, revealed ongoing protection from CHD death and nonfatal MI during an average follow-up of up to 10 years after conclusion of the trial (75). Several studies addressed intensive lipid-lowering therapy. Treatment with rosuvastatin 40 mg (previously reported to cause coronary plaque regression in high-risk patients) to a mean LDL concentration of 78 mg/dl was associated with slowed CIMT progression in low-risk individuals (76). Another investigation demonstrated maintained survival benefits of statin therapy in those subjects with very low LDL levels (⬍60 mg/dl) (77). A meta-analysis of 6 trials enrolling ⬎28,000 subjects reported a decrease in major cardiovascular events with intensive statin therapy in patients with either unstable or stable disease, but reductions in all-cause mortality only in the former (78). Accordingly, costeffectiveness of routine high-dose statins was high in the context of acute coronary syndromes but questionable for stable patients (79).
950
Figure 8
Sanz et al. Year in Atherothrombosis
Molecular Imaging of Macrophages With the Iodinated Contrast Agent N1177
Intracytoplasmic dark granules corresponding to the contrast agent can be noted after incubation of macrophages in vitro with N1177 (A). (B to D) Correspond to in-vivo axial computed tomographic images of the abdominal aorta (arrowheads) in atherosclerotic rabbits obtained before (B), during (C), and 2 h after the administration of N1177 (D). Late, selective enhancement of the vessel wall can be noted (D). (E) Demonstrates the regions of high macrophage density in red (arrow) superimposed on the aortic angiography. Modified, with permission, from Hyafil et al. (65).
Current guidelines for cardiovascular prevention focus mainly on LDL cholesterol, but evidence has accumulated on the growing importance of high-density lipoprotein (HDL) cholesterol as a therapeutic target. A post-hoc analysis of 4 trials performing serial coronary IVUS in 1,455 patients with baseline LDL and HDL concentrations of 124 and 45.1 mg/dl, respectively, reported that regression ⱖ5% in atheroma volume occurred if LDL levels decreased below 87.5 mg/dl and HDL increased by ⬎7.5% (80). The clinical relevance of small changes in HDL cholesterol levels with statin therapy was highlighted in a sub-analysis of CHD patients enrolled in the TNT (Treating to New Targets) trial that demonstrated a 1.1% reduction in the
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
5-year risk of major cardiovascular events per 1 mg/dl increment in HDL concentration (81). Importantly, this beneficial effect persisted after adjustment for multiple covariates and in subjects with very low LDL levels (Fig. 9). However, the ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) trial was prematurely stopped because of increased mortality associated with torcetrapib, a cholesterylester transfer protein inhibitor with potent HDLraising properties. The ILLUMINATE trial randomized 15,067 patients with high-risk (defined as a history of CVD or diabetes) to atorvastatin (to a target LDL ⬍100 mg/dl) alone or in combination with torcetrapib. Despite the 72% increment in HDL and 25% reduction in LDL levels, the torcetrapib arm experienced a 25% increase in major cardiovascular events (6.2% vs. 5%, p ⬍ 0.001) and a 58% increase in total mortality (1.2% vs. 0.8%, p ⫽ 0.006), which included cardiovascular and noncardiovascular causes (82). Imaging studies shed further light on potential reasons for the failure of torcetrapib: when evaluating the 2-year rate progression of atherosclerotic burden, no effect could be detected with either carotid ultrasound (83,84) or coronary IVUS (85). Post-hoc analyses of the ILLUMINATE trial (82) raised the hypothesis that the deleterious effects of torcetrapib may be secondary, at least in part, to activation of the renin-angiotensin-aldosterone system rather than to dysfunctional HDL, although further research is warranted. An alternative approach to augment HDL levels was evaluated in 187 patients with acute coronary syndromes, randomized to receive 4 weekly infusions of placebo or recombinant HDL containing wild-type apoA-I. Serial IVUS demonstrated a 1.6% reduction in percentage atheroma volume for the placebo group and 3.4% for the active arm (significant vs. baseline but not in comparison with placebo). However, there were significant changes in plaque characteristics and luminal narrowing that suggested favorable effects of HDL (86). In agreement with these findings, 2 infusions of exogenous apoA-IMilano in experimentally induced atherosclerosis caused not only disease regression but also a shift to a more stable plaque phenotype as evidenced by reductions in macrophage density and expression of matrix metalloproteinase-2, tissue factor, or monocyte chemoattractant protein-1 (87). Antithrombotic therapy. A post-hoc analysis of the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial suggested that dual antiplatelet therapy with aspirin and clopidogrel may be superior to aspirin alone in the subgroup of symptomatic patients with highest risk (defined as documented peripheral arterial disease, MI, or ischemic stroke) (88). Improved dual antithrombotic therapy was evaluated in TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction)-38. Prasugrel, a novel thienopyridine
Sanz et al. Year in Atherothrombosis
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
951
Summary Outcomes in the COURAGE Trial Table 1
Summary Outcomes in the COURAGE Trial Medical Therapy (n ⴝ 1,138)
Hazard Ratio (95% CI)
p Value
Death and nonfatal MI
19%
18.5%
1.05 (0.87–1.27)
0.62
Death, MI, and stroke
20%
19.5%
1.05 (0.87–1.27)
0.62
Hospitalization for acute coronary syndrome
12.4%
11.8%
1.07 (0.84–1.37)
0.56 0.38
Outcome
Death
PCI (n ⴝ 1,149)
7.6%
8.3%
0.87 (0.65–1.16)
Nonfatal MI
13.2%
12.3%
1.13 (0.89–1.43)
0.33
Revascularization
21.1%
32.6%
0.60 (0.51–0.71)
⬍0.001
CI ⫽ confidence interval; COURAGE ⫽ Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention.
with more potent, rapid and consistent antiplatelet effects, was compared with clopidogrel in 13,608 patients with acute coronary syndromes undergoing percutaneous coro-
Figure 9
CV Risk and HDL
Multivariate-adjusted risk of major cardiovascular (CV) events across different quintiles (Q) of high-density lipoprotein (HDL) cholesterol levels in 9,770 coronary heart disease patients (A) and in the subgroup with low-density lipoprotein cholesterol ⬍70 mg/dl (B). Abbreviations as in Figure 3. Modified, with permission, from Barter et al. (81).
nary intervention. After a median follow-up of 15 months, prasugrel resulted in a 19% relative reduction in the risk of the primary efficacy end point, at the expense of a 32% relative increase in major bleeding (Fig. 10). Considering both end points, there was a net clinical benefit of prasugrel (hazard ratio 0.87; p ⫽ 0.004) (89). Other important advances in antithrombotic therapy of acute coronary syndromes (addressed in other issues of this series) included direct thrombin inhibitors (bivalirudin) and factor Xa inhibitors (fondaparinux) (90,91). In the specific group of patients with peripheral arterial disease, the addition of oral anticoagulation to standard antiplatelet therapy increased the risk of life-threatening bleeding and did not prevent major cardiovascular events (92). CVD and diabetes. The communication of potentially harmful cardiovascular effects of thiazolidinediones triggered one of the most heated debates in 2007. A post-hoc meta-analysis of 42 trials comparing rosiglitazone (n ⫽ 15,565) with other oral antidiabetic drugs or placebo (n ⫽ 12,282) reported an odds ratio of 1.43 for MI (p ⫽ 0.03), and of 1.64 for cardiovascular death (p ⫽ 0.06) (93). The limitations of this analysis were quickly pointed out: inclusion of short-term, heterogeneous studies; inconsistent outcome adjudication; small absolute numbers of events; or use of trial summary results rather than patient-level data (94). Repeated analysis of the same studies with different statistical methodology yielded lower, nonsignificant odds ratios (95). However, a more restringing meta-analysis of only randomized trials that evaluated pre-specified, independently adjudicated outcomes in type 2 diabetes (n ⫽ 14,291) found a similar 42% increase in the risk of MI and doubled risk of heart failure, but not of cardiovascular mortality (96). The debate prompted an interim analysis of the ongoing, multicenter RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial, specifically designed to test the drug’s cardiovascular safety. The increase in adverse outcomes associated with rosiglitazone could not be confirmed (with the exception of heart failure) although insufficient power at that point precluded reaching firm conclusions (97). Moreover, a large observational study in ⬎160,000 individuals failed to detect higher rates of MI (98). The Food and Drug Administration’s final decision was to keep rosiglitazone in the market adding a label warning of increased risk of heart failure and
952
Sanz et al. Year in Atherothrombosis
Figure 10
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
Efficacy and Safety of Prasugrel Versus Clopidogrel in ACS
Cumulative rates of the primary efficacy end point (cardiovascular death, nonfatal MI, or nonfatal stroke) and key safety end point (major bleeding) in the TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction)-38 trial. ACS ⫽ acute coronary syndromes; CI ⫽ confidence interval. Modified, with permission, from Wiviott et al. (89).
potentially also of myocardial ischemia, particularly in patients taking insulin or nitrates (99). To address whether these effects are drug or class specific, a subsequent metaanalysis of 19 randomized controlled trials testing pioglitazone (n ⫽ 16,390) showed overall protective cardiovascular influence (18% reduction in the combined end point of death, MI, or stroke) that might be explained by the more favorable lipid profile changes induced by pioglitazone in comparison with rosiglitazone (100). Finally, the ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) trial (101) randomized ⬎11,000 patients with type 2 diabetes plus other risk factors or established CVD to placebo or a fixed combination of perindopril and indapamide (regardless of the presence of hypertension or use of antihypertensive drugs). After a mean follow-up of 4.3 years, the active arm experienced a significant 9% reduction in a composite end point of major macro- and microvascular complications and an 18% reduction in cardiovascular death, which might be due to the lower blood pressure achieved with the combination therapy.
Conclusions Numerous advances in atherothrombosis took place in 2007, including prevention and promotion of health, bioimaging, and genetics. Antiatherosclerotic therapies were particularly put to the test: the importance of intensive medical management (COURAGE), the failure of torcetrapib (ILLUMINATE), the still controversial future of rosiglitazone, and novel antithrombotic drugs like prasugrel constituted the highlights of an active and exciting year.
Reprint requests and correspondence: Dr. Valentin Fuster, Cardiovascular Institute, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, New York 10029. E-mail: [email protected]. REFERENCES
1. Davies AR, Smeeth L, Grundy EM. Contribution of changes in incidence and mortality to trends in the prevalence of coronary heart disease in the UK: 1996 –2005. Eur Heart J 2007;28:2142–7. 2. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980 –2000. N Engl J Med 2007;356: 2388 –98. 3. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69 –171. 4. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297: 1197–206. 5. Gibbons RJ. Leading the elephant out of the corner: the future of health care: presidential address at the American Heart Association 2006 Scientific Sessions. Circulation 2007;115:2221–30. 6. Fuster V, Voute J, Hunn M, Smith SC Jr. Low priority of cardiovascular and chronic diseases on the global health agenda: a cause for concern. Circulation 2007;116:1966 –70. 7. Fox KAA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999 –2006. JAMA 2007;297:1892–900. 8. Fox CS, Coady S, Sorlie PD, et al. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart study. Circulation 2007;115:1544 –50. 9. Hayman LL, Meininger JC, Daniels SR, et al. Primary prevention of cardiovascular disease in nursing practice: focus on children and youth: a scientific statement from the American Heart Association Committee on Atherosclerosis, Hypertension, and Obesity in Youth of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, Council on Epidemiology and Prevention, and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116:344 –57. 10. Balkau B, Deanfield JE, Despres J-P, et al. International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circum-
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
11. 12. 13. 14.
15.
16.
17.
18. 19. 20. 21.
22. 23. 24.
25. 26.
27.
28.
29.
ference, cardiovascular disease, and diabetes mellitus in 168 000 primary care patients in 63 countries. Circulation 2007;116:1942–51. Frieden TR, Bloomberg MR. How to prevent 100 million deaths from tobacco. Lancet 2007;369:1758 – 61. Kallio K, Jokinen E, Raitakari OT, et al. Tobacco smoke exposure is associated with attenuated endothelial function in 11-year-old healthy children. Circulation 2007;115:3205–12. Schroeder SA. Shattuck lecture. We can do better—improving the health of the American people. N Engl J Med 2007;357:1221– 8. Keevil JG, Cullen MW, Gangnon R, McBride PE, Stein JH. Implications of cardiac risk and low-density lipoprotein cholesterol distributions in the United States for the diagnosis and treatment of dyslipidemia: data from National Health and Nutrition Examination Survey 1999 to 2002. Circulation 2007;115:1363–70. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2007;28:2375– 414. World Health Organization. Prevention of cardiovascular disease: pocket guidelines for assessment and management of cardiovascular risk. Available at: http://www.who.int/cardiovascular_diseases/ guidelines/PocketGL.ENGLISH.AFR-D-E.rev1.pdf. Accessed December 19, 2007. Sniderman AD, Holme I, Aastveit A, Furberg C, Walldius G, Jungner I. Relation of age, the apolipoprotein B/apolipoprotein A-I ratio, and the risk of fatal myocardial infarction and implications for the primary prevention of cardiovascular disease. Am J Cardiol 2007;100:217–21. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299 –308. See R, Abdullah SM, McGuire DK, et al. The association of differing measures of overweight and obesity with prevalent atherosclerosis: the Dallas Heart study. J Am Coll Cardiol 2007;50:752–9. Ingelsson E, Sullivan LM, Fox CS, et al. Burden and prognostic importance of subclinical cardiovascular disease in overweight and obese individuals. Circulation 2007;116:375– 84. Pou KM, Massaro JM, Hoffmann U, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart study. Circulation 2007;116:1234 – 41. Gustafson B, Hammarstedt A, Andersson CX, Smith U. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 2007;27:2276 – 83. Halton TL, Willett WC, Liu S, et al. Low-carbohydrate-diet score and the risk of coronary heart disease in women. N Engl J Med 2006;355:1991–2002. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle study (AusDiab). Circulation 2007; 116:151–7. Liu J, Grundy SM, Wang W, et al. Ten-year risk of cardiovascular incidence related to diabetes, prediabetes, and the metabolic syndrome. Am Heart J 2007;153:552– 8. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49: 403–14. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds risk score. JAMA 2007;297:611–9. Guttormsen BN, Stein JH, McBride PE, Cullen MW, Gangnon R, Keevil JG. Rationale for targeted rather than population based screening with C-reactive protein using the National Health and Nutrition Examination Survey (1999 to 2002). Am J Cardiol 2007; 100:1130 –3. Cao JJ, Arnold AM, Manolio TA, et al. Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health study. Circulation 2007;116:32– 8.
Sanz et al. Year in Atherothrombosis
953
30. Lange LA, Carlson CS, Hindorff LA, et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA 2006;296:2703–11. 31. Emberson JR, Ng LL, Armitage J, Bowman L, Parish S, Collins R. N-terminal pro-B-type natriuretic peptide, vascular disease risk, and cholesterol reduction among 20,536 patients in the MRC/BHF Heart Protection study. J Am Coll Cardiol 2007;49:311–9. 32. Olsen MH, Hansen TW, Christensen MK, et al. N-terminal pro-brain natriuretic peptide, but not high sensitivity C-reactive protein, improves cardiovascular risk prediction in the general population. Eur Heart J 2007;28:1374 – 81. 33. Ingelsson E, Pencina MJ, Tofler GH, et al. Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring study. Circulation 2007;116:984 –92. 34. Wilson AM, Kimura E, Harada RK, et al. Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies. Circulation 2007;116:1396 – 403. 35. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 2006;355:2631–9. 36. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GD, Fowkes FG. Relative value of inflammatory, hemostatic, and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery study. Circulation 2007;115:2119 –27. 37. Shantsila E, Watson T, Lip GYH. Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol 2007;49:741–52. 38. Sorrentino SA, Bahlmann FH, Besler C, et al. Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 2007;116:163–73. 39. Levy AP, Purushothaman KR, Levy NS, et al. Downregulation of the hemoglobin scavenger receptor in individuals with diabetes and the Hp 2-2 genotype: implications for the response to intraplaque hemorrhage and plaque vulnerability. Circ Res 2007;101:106 –10. 40. Morgan TM, Krumholz HM, Lifton RP, Spertus JA. Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. JAMA 2007;297:1551– 61. 41. Arnett DK, Baird AE, Barkley RA, et al. Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation 2007;115:2878 –901. 42. Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. N Engl J Med 2007;357:443–53. 43. Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007;316:1341–5. 44. Kathiresan S, Larson MG, Keyes MJ, et al. Assessment by cardiovascular magnetic resonance, electron beam computed tomography, and carotid ultrasonography of the distribution of subclinical atherosclerosis across Framingham risk strata. Am J Cardiol 2007;99: 310 – 4. 45. Kim LG, Scott RAP, Ashton HA, Thompson SG, for the Multicentre Aneurysm Screening Study Group. A sustained mortality benefit from screening for abdominal aortic aneurysm. Ann Intern Med 2007;146:699 –706. 46. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007; 115:459 – 67. 47. Lamina C, Meisinger C, Heid IM, et al. Association of anklebrachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up. Eur Heart J 2006;27:2580 –7. 48. Sen S, Hinderliter A, Sen PK, et al. Aortic arch atheroma progression and recurrent vascular events in patients with stroke or transient ischemic attack. Circulation 2007;116:928 –35. 49. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the
954
50. 51. 52. 53. 54.
55.
56. 57. 58.
59.
60.
61. 62. 63.
64.
65. 66. 67. 68.
69.
Sanz et al. Year in Atherothrombosis American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography). J Am Coll Cardiol 2007;49:378 – 402. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol 2007;49:1860 –70. Rozanski A, Gransar H, Wong ND, et al. Clinical outcomes after both coronary calcium scanning and exercise myocardial perfusion scintigraphy. J Am Coll Cardiol 2007;49:1352– 61. Cassidy-Bushrow AE, Bielak LF, Sheedy PF 2nd, et al. Coronary artery calcification progression is heritable. Circulation 2007;116: 25–31. Hoffmann B, Moebus S, Mohlenkamp S, et al. Residential exposure to traffic is associated with coronary atherosclerosis. Circulation 2007;116:489 –96. Meijboom WB, van Mieghem CAG, Mollet NR, et al. 64-slice computed tomography coronary angiography in patients with high, intermediate, or low pretest probability of significant coronary artery disease. J Am Coll Cardiol 2007;50:1469 –75. Butler J, Shapiro M, Reiber J, et al. Extent and distribution of coronary artery disease: a comparative study of invasive versus noninvasive angiography with computed angiography. Am Heart J 2007;153:378 – 84. Cheruvu PK, Finn AV, Gardner C, et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. J Am Coll Cardiol 2007;50:940 –9. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic angiography for prediction of all-cause mortality. J Am Coll Cardiol 2007;50:1161–70. Kim WY, Astrup AS, Stuber M, et al. Subclinical coronary and aortic atherosclerosis detected by magnetic resonance imaging in type 1 diabetes with and without diabetic nephropathy. Circulation 2007; 115:228 –35. Tahara N, Kai H, Yamagishi S, et al. Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. J Am Coll Cardiol 2007;49:1533–9. Rudd JH, Myers KS, Bansilal S, et al. (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trials. J Am Coll Cardiol 2007;50:892– 6. Tahara N, Kai H, Ishibashi M, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2006;48:1825–31. Nicholls SJ, Tuzcu EM, Wolski K, et al. Coronary artery calcification and changes in atheroma burden in response to established medical therapies. J Am Coll Cardiol 2007;49:263–70. Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007;50:933–9. Amirbekian V, Lipinski MJ, Briley-Saebo KC, et al. Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI. Proc Natl Acad Sci U S A 2007;104: 961– 6. Hyafil F, Cornily JC, Feig JE, et al. Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nat Med 2007;13:636 – 41. Kaufmann BA, Sanders JM, Davis C, et al. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation 2007;116:276 – 84. Flaumenhaft R, Tanaka E, Graham GJ, et al. Localization and quantification of platelet-rich thrombi in large blood vessels with near-infrared fluorescence imaging. Circulation 2007;115:84 –93. Niinikoski H, Lagstrom H, Jokinen E, et al. Impact of repeated dietary counseling between infancy and 14 years of age on dietary intakes and serum lipids and lipoproteins: the STRIP study. Circulation 2007;116:1032– 40. Hu G, Tuomilehto J, Borodulin K, Jousilahti P. The joint associations of occupational, commuting, and leisure-time physical activity, and the Framingham risk score on the 10-year risk of coronary heart disease. Eur Heart J 2007;28:492– 8.
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55 70. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. 71. Kereiakes DJ, Teirstein PS, Sarembock IJ, et al. The truth and consequences of the COURAGE trial. J Am Coll Cardiol 2007;50: 1598 – 603. 72. Hueb W, Lopes NH, Gersh BJ, et al. Five-year follow-up of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2007;115:1082–9. 73. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA 2007;297:177– 86. 74. Wood DA. Clinical reality of coronary prevention in Europe: a comparison of EUROASPIRE I, II and III surveys. Available at: http://www.cardiosource.com/rapidnewssummaries/index.asp?EID⫽ 27&DoW⫽Sun&SumID⫽216. Accessed December 19, 2007. 75. Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med 2007;357:1477– 86. 76. Crouse JR 3rd, Raichlen JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR trial. JAMA 2007; 297:1344 –53. 77. Leeper NJ, Ardehali R, deGoma EM, Heidenreich PA. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation 2007;116:613– 8. 78. Afilalo J, Majdan AA, Eisenberg MJ. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials. Heart 2007;93:914 – 21. 79. Chan PS, Nallamothu BK, Gurm HS, Hayward RA, Vijan S. Incremental benefit and cost-effectiveness of high-dose statin therapy in high-risk patients with coronary artery disease. Circulation 2007; 115:2398 – 409. 80. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499 –508. 81. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301–10. 82. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357: 2109 –22. 83. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;356:1620 –30. 84. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007;370:153– 60. 85. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356: 1304 –16. 86. Tardif JC, Gregoire J, L’Allier PL, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675– 82. 87. Ibanez B, Vilahur G, Cimmino G, et al. Rapid change in plaque size, composition and molecular footprint following recombinant ApoAIMilano (ETC-216) administration. J Am Coll Cardiol 2008. In press. 88. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49: 1982– 8. 89. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. 90. Mehta SR, Granger CB, Eikelboom JW, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol 2007;50:1742–51. 91. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203–16.
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55 92. Anand S, Yusuf S, Xie C, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007;357:217–27. 93. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. 94. Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007;356:2522– 4. 95. Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med 2007;147:578 – 81. 96. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189 –95. 97. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 2007;357:28 –38.
Sanz et al. Year in Atherothrombosis
955
98. Rosen CJ. The rosiglitazone story—lessons from an FDA advisory committee meeting. N Engl J Med 2007;357:844 – 6. 99. Food and Drug Administration. Information for Healthcare Professionals. Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl). Available at: http://www.fda.gov/cder/drug/InfoSheets/ HCP/rosiglitazone200707HCP.htm#2007_5. Accessed December 19, 2007. 100. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007;298:1180 – 8. 101. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370: 829 – 40.
Vol. 51, No. 9, 2008 ISSN 0735-1097/08/$34.00 doi:10.1016/j.jacc.2007.12.018
YEAR IN CARDIOLOGY SERIES
The Year in Atherothrombosis Javier Sanz, MD, Pedro R. Moreno, MD, FACC, Valentin Fuster, MD, PHD, FACC New York, New York The present review aims to summarize relevant studies published during the last year in the field of atherothrombosis. A special emphasis was placed on the promotion of cardiovascular health worldwide, as well as on the need for a progressive shift from the treatment of advanced disease to early detection and enhanced prevention. Epidemiology and Public Health Impact Important information on the magnitude of the burden of cardiovascular disease (CVD) became available in 2007. During the last 2 decades, coronary heart disease (CHD) age-specific death rates fell by ⬎40% in high-income countries (1,2). Prolonged survival has translated into growing disease prevalence and number of hospitalizations, with much smaller reductions in absolute mortality and staggering financial burden: the estimated annual cost of CVD in the U.S. is $431 billion (1,3). The 1-year incidence of death, myocardial infarction (MI), stroke, or hospitalization for an atherothrombotic event is 14% for patients with established atherosclerotic disease, and 5% for patients with multiple (⬎2) risk factors, according to an international registry (4). With continuing increase in expenditure and progressive aging of the population, the present healthcare system appears unsustainable in the long run (5). The importance of considering CVD a global health priority was emphasized: CVD is the main killer also in low- and middleincome countries, and causes 3 times more deaths than the most lethal infectious diseases combined. In developing countries, CVD affects younger people of working age and has additional economic impact (6). Up to 50% of the reduction in age-adjusted mortality from CHD can be attributed to the application of evidencebased therapies rather than to effective prevention (1,2,7). Although the remaining improvement in survival can be explained by reductions in some risk factors, obesity and diabetes markedly increased, as well as the burden of CVD attributable to diabetes (2,8). Of major concern, risk profile worsened in children and adolescents: hypertension, obesity, diabetes, and physical inactivity escalated, whereas cholesterol levels and tobacco use remained unchanged (9). In From The Zena and Michael A. Wiener Cardiovascular Institute/Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, New York. Manuscript received November 12, 2007; accepted December 13, 2007.
developing regions, the prevalence of traditional risk factors is on the rise in both adults and the young (6). According to a survey in ⬎168,000 primary care patients in 63 countries worldwide, ⬎60% of men and ⬎50% of women are either overweight or obese in all regions except southern and eastern Asia (10). Approximately 25% of the world population smokes, with two-thirds living in 15 low- and middle-income countries (11). Tobacco smoke exposure was shown to cause dose-dependent endothelial dysfunction in children (12). Smoking and obesity/inactivity have become the 2 leading modifiable causes of premature death (13). Early Detection and Risk Assessment Traditional risk factors. Traditional risk factors continued to be the cornerstone of prevention and risk stratification. A report from NHANES (National Health and Nutrition Examination Survey) estimated that the percentages of adult Americans falling into the low, moderate, moderateto-high, high, and very-high risk categories are 61.1%, 17.2%, 5.4%, 10.6%, and 5.7%, respectively (Fig. 1) (14). These findings suggest that the “intermediate-risk” group may be smaller than previously thought. The European Society of Cardiology updated region-specific charts for predicting the 10-year risk of a first fatal atherosclerotic event based on age, gender, smoking habit, systolic blood pressure, and total cholesterol (15). In an attempt to improve primary prevention worldwide, the World Health Organization proposed the use of similar simplified region-specific charts that also consider the presence of diabetes (16). A number of studies evaluated the roles of lipids in cardiovascular risk. The relationship between age, lipid profile, and incident fatal MI was evaluated in ⬎128,000 subjects followed for a mean of 10.3 years. Most of the excess risk associated with age could be attributed to long-term exposure to a proatherogenic lipid environment, thus suggesting that it is potentially modifiable (17). Independent, long-term associations with MI, CHD, and death were also described for nonfasting concentrations of serum triglycerides in both men and women (18). Several studies addressed the relationship between obesity and CVD. The waist-to-hip ratio was independently associated with the presence of coronary calcium by computed
Sanz et al. Year in Atherothrombosis
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
Figure 1
Distribution of CV Risk and LDL Levels in American Adults
Absolute numbers of individuals (in millions) for each National Cholesterol Education Program Adult Treatment Panel III risk category and level of low-density lipoprotein cholesterol (LDL-C) are shown. Those meeting the recommended LDL-C target levels are highlighted in green, those requiring therapeutic changes are indicated in red, and those in whom therapeutic changes could be appropriate are shown in yellow. The majority of the population falls into the low-risk category; however, it is evident that most individuals with the highest risk do not meet the desired LDL-C goal. CV ⫽ cardiovascular. Reprinted, with permission, from Keevil et al. (14).
tomography (CT) and of aortic plaque by magnetic resonance imaging (MRI) (19). The contribution of subclinical CVD to future events in obese individuals was highlighted in the Framingham Offspring study (20). Both abdominal visceral and subcutaneous adiposity correlated with markers of inflammation or oxidative stress (21), reinforcing the proatherogenic state associated with obesity (Fig. 2) (22). Regarding glucose metabolism, a high dietary glycemic load was independently associated with increased risk of CHD in women (23). Elevated fasting glucose independently predicted heightened CVD mortality in 10,428 Australian subjects (24), but this risk was markedly mitigated in the absence of the metabolic syndrome in another investigation including ⬎30,000 Chinese individuals (25). A metaanalysis of 37 longitudinal studies and ⬎173,000 patients reported a relative risk of 1.78 for cardiovascular events and death associated with the metabolic syndrome, which remained significant even after adjustment for its individual components (26). Serum biomarkers. Among the many reports published in 2007 evaluating the diagnostic and prognostic significance of numerous biomarkers, several studies deserve special consideration. A novel algorithm from the Women’s Health study including C-reactive protein (CRP) and, in diabetic patients, hemoglobin A1C was developed and validated. It resulted in reclassification of risk category in 30% to 45% of intermediate-risk women, with superior predictive ability than the NCEP ATP-III (National Cholesterol Education Program Adult Treatment Panel III) model (27). Arguing
945
against routine CRP measurement, NHANES investigators estimated that such approach would lead to modification of the target low-density lipoprotein (LDL) cholesterol only in 3.1% of the U.S. adults (28). In elderly participants of the Cardiovascular Health study without manifest CVD, increased levels of CRP were associated with impaired prognosis only in patients with subclinical atherosclerosis as determined by the carotid intima-media thickness (CIMT) (29). Data from the same study suggested that polymorphisms of the CRP gene contribute significantly to both plasmatic concentrations and cardiovascular risk, but not to CIMT (30). The strong prognostic implications of increased levels of N-terminal pro-brain natriuretic peptide (BNP) were highlighted in ⬎20,000 high-risk individuals from the Heart Protection study. After an average follow-up of 5 years, elevated N-terminal pro-BNP concentrations indicated markedly increased risk of not only heart failure but also occlusive atherothrombotic events (Fig. 3) (31). Comparable independent predictive ability, superior to CRP, was confirmed in a population-based study with a median follow-up of 9.4 years (32). In participants of the Framingham Offspring study in whom multiple markers of inflammation, neurohormonal activity, and endothelial dysfunction were quantified, increased levels of aldosterone and plasminogen activator inhibitor-1 were independent predictors of incident metabolic syndrome (33). Additionally, a preliminary study demonstrated correlations of plasma levels of beta2-microglobulin with the ankle-brachial index and functional capacity, and suggested a potential role specifically for the diagnosis of peripheral arterial disease (34).
Figure 2
Adipocyte Abnormalities in Obesity and the Proatherogenic Role of Adiposity
Progressive weight gain leads to adipocyte enlargement and a pro-inflammatory state with increased macrophage activation, secretion of chemokines and cytokines, and endothelial damage. ER ⫽ endoplasmic reticulum; IKK ⫽ IkappaB kinase; IL ⫽ interleukin; JNK ⫽ c-Jun N-terminal kinase; MCP ⫽ monocyte chemoattractant protein; SAA ⫽ serum amyloid A; TLR ⫽ toll-like receptor; TNF ⫽ tumor necrosis factor. Reprinted, with permission, from Gustafson et al. (22).
946
Figure 3
Sanz et al. Year in Atherothrombosis
BNP and CV Risk
Multivariate-adjusted relative risks of various cardiovascular (CV) events according to baseline levels of N-terminal (N) pro-brain natriuretic peptide (BNP). CI ⫽ confidence interval. Modified, with permission, from Emberson et al. (31).
Two studies questioned the prognostic value of individual biomarkers in the general population and suggested some, although modest, additive predictive ability of multimarker approaches over conventional risk stratification. Ten biomarkers were measured in 3,209 patients followed for a median of 7.4 years. The adjusted hazard ratio of death was 4.08 for the top versus the 2 lower quintiles of a multimarker score containing BNP, homocysteine, CRP, renin, and urinary albumin-to-creatinine ratio; the hazard ratio of major cardiovascular events was 1.84 for a score containing BNP and urinary albumin-to-creatinine ratio (35). In a second investigation the ankle-brachial index and 17 biomarkers were quantified in 1,592 patients followed for a mean of 17 years. A score including interleukin-6, intercellular adhesion molecule-1, lipoprotein(a), and tissue plasminogen activator provided some added value for the prediction of major cardiovascular events (36). Circulating endothelial progenitor cells and genetic markers. There is increasing evidence of the crucial role of endothelial progenitor cells in the repair of chronic endothelial injury secondary to cardiovascular risk factors. Both in apparently healthy individuals and in those with CVD there is an inverse correlation between the number and functional activity of endothelial progenitor cells and risk profile, indicating a delicate balance between regenerative capacity and development of disease (37). Enhancing the number and function of circulating progenitor cells is, therefore, an attractive therapeutic target, and promising
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
preliminary results with peroxisome proliferator-activated receptor-gamma agonists (glitazones) were reported (38). Homozygosity for the haptoglobin 2 gene was associated with down-regulation of the hemoglobin scavenger receptor in diabetic patients, suggesting that inability to clear toxicfree hemoglobin from intraplaque hemorrhage may be an important contributor to diabetic risk (39). In an attempt to validate previously described genetic risk factors for CVD, one investigation tested 85 variants of 70 genes in 811 patients with acute coronary syndromes and 650 control subjects. Only one variant in the beta-fibrinogen gene was marginally different between the groups (40). The inability to replicate prior associations in different populations highlighted the complexity of the interactions between multiple genetic and environmental factors, and suggests that extensive research will be necessary before the application of genetic profiling in clinical practice (41). Identification of meaningful variants will require powerful genotyping tools and validation in different populations. One such study performing genome-wide analysis compared ⬎500,000 single-nucleotide polymorphisms in 2 independent populations of patients with CHD and control subjects. Of the 7 loci that were identified as high-likelihood candidates, the strongest association was noted for a region of chromosome 9 that encodes genes involved in cell cycle regulation (42). Similar multipopulation genome-wide association studies allowed for the identification of at least 10 loci linked to type 2 diabetes, each exerting a modest effect on risk (Fig. 4) (43). Detection of subclinical disease and imaging. In apparently healthy individuals, the number of imaging tests revealing extensive atherosclerosis correlated with the Framingham score. However, there were frequent discrepancies between estimated risk and disease burden (Fig. 5) and different modalities agreed poorly with one another, highlighting the challenge of inferring information of one vascular bed from the status of another (44). Several studies addressed the prognostic implications of detecting subclinical disease in the general population. A multicenter trial randomized ⬎67,000 men of age 65 to 74 years to receive or not an invitation for ultrasonographic screening of abdominal aneurysm. After a mean follow-up of 7.1 years, aneurysm-related mortality was halved in the group invited for screening, an approach that additionally proved highly cost-effective (45). According to a meta-analysis of 8 studies enrolling ⬎31,000 individuals, the age- and genderadjusted hazard ratios of 0.1 mm increment in common CIMT were 1.15 and 1.18, respectively, for incident MI and stroke (46). The presence of occlusive and sub-occlusive peripheral arterial disease independently predicted MI and death in 1,325 individuals in whom the ankle-brachial index and carotid and femoral plaques by ultrasound were evaluated (47). Additionally, in 117 patients with prior stroke or transient ischemic attack and serial transesophageal echocardiograms, progression of aortic atheroma over 12 months was associated with an almost 6-fold increase in risk of
Sanz et al. Year in Atherothrombosis
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
Figure 4
Genetic Risk of T2D
The risk of type 2 diabetes (T2D) is estimated from a logistic regression model containing 10 susceptibility genetic variants. The x axis contains 20 equal intervals of predicted T2D risk derived from the model. The y axis shows the number (with 95% confidence limits) of T2D cases within each predicted risk interval. The horizontal dashed line indicates the sample prevalence of T2D. There is a 4-fold increase in risk of T2D (from 5% to 20%) from the lowest to the highest predicted risk categories. Modified, with permission, from Scott et al. (43). Reprinted with permission from AAAS.
subsequent cardiovascular events during a median follow-up of 1.7 years (48). The field of cardiac CT was particularly active. A new expert consensus document emphasized the incremental predictive value of calcium scoring over conventional risk factors for the occurrence of cardiovascular death or MI in asymptomatic individuals, particular those at intermediate
Figure 5
947
risk (49). This prognostic ability was reiterated in the largest series available so far (⬎25,000 patients followed for 6.8 ⫾ 3 years), which showed markedly reduced adjusted survival with increasing calcium scores (50), a risk that may be modulated by the presence of concomitant ischemia (51). Family history was shown to contribute to both development and progression of coronary calcification (52). Conversely, the influence of environmental factors was highlighted by the positive association between the calcium score and air pollution (53). Regarding contrast-enhanced coronary CT angiography, a study of 254 patients with chest pain suggested that CT is useful in subjects with low or intermediate pre-test probability, in whom a normal scan reliably rules out disease and a positive result should prompt additional testing (54). Importantly, CT was able to detect atherosclerosis, including calcified and non-calcified nonstenotic plaques, in ⬎50% of the segments considered normal by invasive catheterization (55). Computed tomography is more accurate for the evaluation of plaques in the proximal coronary segments, the most common location for thin-cap fibroatheromas and plaque ruptures as confirmed in a recent autopsy series (56). The prognostic value of CT coronary angiography was highlighted in a retrospective study of 1,127 symptomatic individuals. Besides stenosis severity and proximal disease location, the presence of ⬎5 segments with any detectable plaque was identified as an independent predictor of all-cause mortality in multivariate analysis. Survival in the absence of plaque in the left main or left anterior descending arteries surpassed 97% after an average follow-up of 15 months (57). Black-blood MRI for noninvasive plaque quantification in the coronary arteries and the aorta was employed in another investigation of type 1 diabetes mellitus. Aortic plaque extent was similar in patients with or without nephropathy, but the former had significantly increased coronary disease burden (Fig. 6), which additionally correlated with diabetes duration and total cholesterol level (58).
Distribution of Atherosclerotic Burden According to Baseline Risk
Proportions of male (A) or female (B) subjects with high atherosclerotic burden (defined as value ⬎80th percentile) in 0, 1, 2, 3, or 4 tests for the presence of subclinical disease: carotid intima-media thickness, magnetic resonance imaging-derived aortic plaque burden, aortic calcium score, and coronary calcium score. Patients are grouped according to their Framingham risk score. Modified, with permission, from Kathiresan et al. (44).
948
Figure 6
Sanz et al. Year in Atherothrombosis
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
MRI-Derived Coronary Plaque Burden
Bright-blood (A and C) and black-blood (B and D) magnetic resonance imaging (MRI) of the right coronary artery (RCA) in a patient with type 1 diabetes and normoalbuminuria (top) and a second patient with diabetic nephropathy (bottom). Both patients have a patent RCA lumen; however, the thickness of the vessel wall is markedly increased in the patient with nephropathy (D, black arrows) in comparison with the patient with normoalbuminuria (B, white arrows). Reproduced, with permission, from Kim et al. (58).
The degree of vascular inflammation assessed with combined CT and 18F-fluorodeoxyglucose positron emission tomography was significantly correlated with the number of components of the metabolic syndrome (59). Another investigation reported excellent interobserver, intraobserver, and interscan reproducibility of this technique (Fig. 7), suggesting a potential role for serial testing (60). In this regard, reductions of vessel wall inflammation after statin therapy could be demonstrated (61). Using intravascular ultrasound (IVUS), it was shown that the progression/ regression in atheroma volume in response to interventions is inversely correlated to the amount of calcification, suggesting that calcified plaques are more resistant to change (62). Optical coherence tomography, an alternative invasive modality with superb spatial resolution, demonstrated superior ability than IVUS or coronary angiography for the detection of plaque rupture/erosion or intracoronary thrombus in patients with acute MI (63). In the field of molecular imaging, successful detection of plaque inflammation with MRI was possible with gadolinium-loaded micelles coupled with antibodies against the macrophage scavenger receptor (64). An alternative approach used CT and a novel iodinated nanoparticulate contrast that is selectively taken up by macrophages to
successfully detect experimental aortic atherosclerosis (Fig. 8) (65). Vascular inflammation in various stages of atherosclerosis could be depicted using ultrasound and microbubbles targeted to vascular cell adhesion molecule-1 in mice (66). In addition, an intraoperative near-infrared fluorescence imaging system and the injection of platelets labeled with a novel fluorophore allowed for the detection of occlusive and nonocclusive thrombi in porcine carotid, femoral, and coronary arteries in vivo (67). Therapy Risk factor management and importance of medical therapy. Reinforcing the relevance of early identification of risk factors, the American Heart Association released recommendations for primary prevention in children and adolescents (9). Dietary counseling starting at infancy and maintained throughout childhood resulted in maintained decreases in total and LDL cholesterol until at least 14 years of age (68). Approximately 34% of American adults have LDL cholesterol levels above the recommended goal, and the number is ⬃75% in those with the highest risk. Moreover, in almost 50%, lower LDL concentrations would be desirable (Fig. 1) (14). Moderate-to-high levels of
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
Figure 7
Sanz et al. Year in Atherothrombosis
949
Vascular Inflammation Demonstrated With PET/CT
Sagittal images of the chest obtained with computed tomography (CT) (left), positron emission tomography (PET) (middle), and the corresponding fused images (PET/CT) (right). The top row shows the baseline scan and the bottom row a follow-up study performed 2 weeks later. Reproducible uptake of 18F-fluorodeoxyglucose in the aortic arch (arrows) can be noted in both scans. A ⫽ anterior; P ⫽ posterior. Reproduced, with permission, from Rudd et al. (60).
physical activity in daily tasks were associated with decreases in coronary events across the spectrum of baseline cardiovascular risk (69). In addition, it was estimated that a 20% decrease in the number of world smokers by 2020 could prevent 100 million premature deaths (11). One of the highlights of 2007 was the publication of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial. Of ⬎35,000 potential candidates, 2,287 patients with stable coronary disease, objective mild/moderate ischemia, and proven severe coronary stenoses were randomized to optimized medical therapy with or without percutaneous intervention (using mainly bare-metal stents). Of note, 58% of the patients had class II/III angina and 69% multivessel disease, including significant stenosis of the proximal left anterior descending artery in ⬃30%. After a median follow-up of 4.6 years, there were no significant differences between the 2 groups in rates of death, MI, stroke, or their combination (Table 1). Patients initially assigned to percutaneous intervention had lower rates of subsequent revascularization and angina, although symptoms decreased significantly in both groups (70). The results of this trial did not come without criticism (71), but overall reinforced the importance of aggressive medical management. Comparable findings came from MASS (Medicine, Angioplasty, or Surgery Study) II, which reported similar 5-year mortality for percutaneous intervention, coronary bypass surgery, or medical therapy as the treatment of stable patients with multivessel coronary disease and preserved ejection fraction, although revascular-
ization provided better symptomatic control (72). Additionally, adherence to therapies of proven benefit was independently associated with improved post-MI survival (73). However, the results of the third EUROASPIRE (European Action on Secondary Prevention through Intervention to Reduce Events-III) survey demonstrated that large proportions of patients with known CHD remain undertreated (74). Lipid therapy. A long-term follow-up of 5,778 men without previous MI enrolled in WOSCOPS (West of Scotland Coronary Prevention Study), which compared pravastatin versus placebo for 5 years, revealed ongoing protection from CHD death and nonfatal MI during an average follow-up of up to 10 years after conclusion of the trial (75). Several studies addressed intensive lipid-lowering therapy. Treatment with rosuvastatin 40 mg (previously reported to cause coronary plaque regression in high-risk patients) to a mean LDL concentration of 78 mg/dl was associated with slowed CIMT progression in low-risk individuals (76). Another investigation demonstrated maintained survival benefits of statin therapy in those subjects with very low LDL levels (⬍60 mg/dl) (77). A meta-analysis of 6 trials enrolling ⬎28,000 subjects reported a decrease in major cardiovascular events with intensive statin therapy in patients with either unstable or stable disease, but reductions in all-cause mortality only in the former (78). Accordingly, costeffectiveness of routine high-dose statins was high in the context of acute coronary syndromes but questionable for stable patients (79).
950
Figure 8
Sanz et al. Year in Atherothrombosis
Molecular Imaging of Macrophages With the Iodinated Contrast Agent N1177
Intracytoplasmic dark granules corresponding to the contrast agent can be noted after incubation of macrophages in vitro with N1177 (A). (B to D) Correspond to in-vivo axial computed tomographic images of the abdominal aorta (arrowheads) in atherosclerotic rabbits obtained before (B), during (C), and 2 h after the administration of N1177 (D). Late, selective enhancement of the vessel wall can be noted (D). (E) Demonstrates the regions of high macrophage density in red (arrow) superimposed on the aortic angiography. Modified, with permission, from Hyafil et al. (65).
Current guidelines for cardiovascular prevention focus mainly on LDL cholesterol, but evidence has accumulated on the growing importance of high-density lipoprotein (HDL) cholesterol as a therapeutic target. A post-hoc analysis of 4 trials performing serial coronary IVUS in 1,455 patients with baseline LDL and HDL concentrations of 124 and 45.1 mg/dl, respectively, reported that regression ⱖ5% in atheroma volume occurred if LDL levels decreased below 87.5 mg/dl and HDL increased by ⬎7.5% (80). The clinical relevance of small changes in HDL cholesterol levels with statin therapy was highlighted in a sub-analysis of CHD patients enrolled in the TNT (Treating to New Targets) trial that demonstrated a 1.1% reduction in the
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
5-year risk of major cardiovascular events per 1 mg/dl increment in HDL concentration (81). Importantly, this beneficial effect persisted after adjustment for multiple covariates and in subjects with very low LDL levels (Fig. 9). However, the ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) trial was prematurely stopped because of increased mortality associated with torcetrapib, a cholesterylester transfer protein inhibitor with potent HDLraising properties. The ILLUMINATE trial randomized 15,067 patients with high-risk (defined as a history of CVD or diabetes) to atorvastatin (to a target LDL ⬍100 mg/dl) alone or in combination with torcetrapib. Despite the 72% increment in HDL and 25% reduction in LDL levels, the torcetrapib arm experienced a 25% increase in major cardiovascular events (6.2% vs. 5%, p ⬍ 0.001) and a 58% increase in total mortality (1.2% vs. 0.8%, p ⫽ 0.006), which included cardiovascular and noncardiovascular causes (82). Imaging studies shed further light on potential reasons for the failure of torcetrapib: when evaluating the 2-year rate progression of atherosclerotic burden, no effect could be detected with either carotid ultrasound (83,84) or coronary IVUS (85). Post-hoc analyses of the ILLUMINATE trial (82) raised the hypothesis that the deleterious effects of torcetrapib may be secondary, at least in part, to activation of the renin-angiotensin-aldosterone system rather than to dysfunctional HDL, although further research is warranted. An alternative approach to augment HDL levels was evaluated in 187 patients with acute coronary syndromes, randomized to receive 4 weekly infusions of placebo or recombinant HDL containing wild-type apoA-I. Serial IVUS demonstrated a 1.6% reduction in percentage atheroma volume for the placebo group and 3.4% for the active arm (significant vs. baseline but not in comparison with placebo). However, there were significant changes in plaque characteristics and luminal narrowing that suggested favorable effects of HDL (86). In agreement with these findings, 2 infusions of exogenous apoA-IMilano in experimentally induced atherosclerosis caused not only disease regression but also a shift to a more stable plaque phenotype as evidenced by reductions in macrophage density and expression of matrix metalloproteinase-2, tissue factor, or monocyte chemoattractant protein-1 (87). Antithrombotic therapy. A post-hoc analysis of the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial suggested that dual antiplatelet therapy with aspirin and clopidogrel may be superior to aspirin alone in the subgroup of symptomatic patients with highest risk (defined as documented peripheral arterial disease, MI, or ischemic stroke) (88). Improved dual antithrombotic therapy was evaluated in TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction)-38. Prasugrel, a novel thienopyridine
Sanz et al. Year in Atherothrombosis
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
951
Summary Outcomes in the COURAGE Trial Table 1
Summary Outcomes in the COURAGE Trial Medical Therapy (n ⴝ 1,138)
Hazard Ratio (95% CI)
p Value
Death and nonfatal MI
19%
18.5%
1.05 (0.87–1.27)
0.62
Death, MI, and stroke
20%
19.5%
1.05 (0.87–1.27)
0.62
Hospitalization for acute coronary syndrome
12.4%
11.8%
1.07 (0.84–1.37)
0.56 0.38
Outcome
Death
PCI (n ⴝ 1,149)
7.6%
8.3%
0.87 (0.65–1.16)
Nonfatal MI
13.2%
12.3%
1.13 (0.89–1.43)
0.33
Revascularization
21.1%
32.6%
0.60 (0.51–0.71)
⬍0.001
CI ⫽ confidence interval; COURAGE ⫽ Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention.
with more potent, rapid and consistent antiplatelet effects, was compared with clopidogrel in 13,608 patients with acute coronary syndromes undergoing percutaneous coro-
Figure 9
CV Risk and HDL
Multivariate-adjusted risk of major cardiovascular (CV) events across different quintiles (Q) of high-density lipoprotein (HDL) cholesterol levels in 9,770 coronary heart disease patients (A) and in the subgroup with low-density lipoprotein cholesterol ⬍70 mg/dl (B). Abbreviations as in Figure 3. Modified, with permission, from Barter et al. (81).
nary intervention. After a median follow-up of 15 months, prasugrel resulted in a 19% relative reduction in the risk of the primary efficacy end point, at the expense of a 32% relative increase in major bleeding (Fig. 10). Considering both end points, there was a net clinical benefit of prasugrel (hazard ratio 0.87; p ⫽ 0.004) (89). Other important advances in antithrombotic therapy of acute coronary syndromes (addressed in other issues of this series) included direct thrombin inhibitors (bivalirudin) and factor Xa inhibitors (fondaparinux) (90,91). In the specific group of patients with peripheral arterial disease, the addition of oral anticoagulation to standard antiplatelet therapy increased the risk of life-threatening bleeding and did not prevent major cardiovascular events (92). CVD and diabetes. The communication of potentially harmful cardiovascular effects of thiazolidinediones triggered one of the most heated debates in 2007. A post-hoc meta-analysis of 42 trials comparing rosiglitazone (n ⫽ 15,565) with other oral antidiabetic drugs or placebo (n ⫽ 12,282) reported an odds ratio of 1.43 for MI (p ⫽ 0.03), and of 1.64 for cardiovascular death (p ⫽ 0.06) (93). The limitations of this analysis were quickly pointed out: inclusion of short-term, heterogeneous studies; inconsistent outcome adjudication; small absolute numbers of events; or use of trial summary results rather than patient-level data (94). Repeated analysis of the same studies with different statistical methodology yielded lower, nonsignificant odds ratios (95). However, a more restringing meta-analysis of only randomized trials that evaluated pre-specified, independently adjudicated outcomes in type 2 diabetes (n ⫽ 14,291) found a similar 42% increase in the risk of MI and doubled risk of heart failure, but not of cardiovascular mortality (96). The debate prompted an interim analysis of the ongoing, multicenter RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial, specifically designed to test the drug’s cardiovascular safety. The increase in adverse outcomes associated with rosiglitazone could not be confirmed (with the exception of heart failure) although insufficient power at that point precluded reaching firm conclusions (97). Moreover, a large observational study in ⬎160,000 individuals failed to detect higher rates of MI (98). The Food and Drug Administration’s final decision was to keep rosiglitazone in the market adding a label warning of increased risk of heart failure and
952
Sanz et al. Year in Atherothrombosis
Figure 10
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
Efficacy and Safety of Prasugrel Versus Clopidogrel in ACS
Cumulative rates of the primary efficacy end point (cardiovascular death, nonfatal MI, or nonfatal stroke) and key safety end point (major bleeding) in the TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction)-38 trial. ACS ⫽ acute coronary syndromes; CI ⫽ confidence interval. Modified, with permission, from Wiviott et al. (89).
potentially also of myocardial ischemia, particularly in patients taking insulin or nitrates (99). To address whether these effects are drug or class specific, a subsequent metaanalysis of 19 randomized controlled trials testing pioglitazone (n ⫽ 16,390) showed overall protective cardiovascular influence (18% reduction in the combined end point of death, MI, or stroke) that might be explained by the more favorable lipid profile changes induced by pioglitazone in comparison with rosiglitazone (100). Finally, the ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) trial (101) randomized ⬎11,000 patients with type 2 diabetes plus other risk factors or established CVD to placebo or a fixed combination of perindopril and indapamide (regardless of the presence of hypertension or use of antihypertensive drugs). After a mean follow-up of 4.3 years, the active arm experienced a significant 9% reduction in a composite end point of major macro- and microvascular complications and an 18% reduction in cardiovascular death, which might be due to the lower blood pressure achieved with the combination therapy.
Conclusions Numerous advances in atherothrombosis took place in 2007, including prevention and promotion of health, bioimaging, and genetics. Antiatherosclerotic therapies were particularly put to the test: the importance of intensive medical management (COURAGE), the failure of torcetrapib (ILLUMINATE), the still controversial future of rosiglitazone, and novel antithrombotic drugs like prasugrel constituted the highlights of an active and exciting year.
Reprint requests and correspondence: Dr. Valentin Fuster, Cardiovascular Institute, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, New York 10029. E-mail: [email protected]. REFERENCES
1. Davies AR, Smeeth L, Grundy EM. Contribution of changes in incidence and mortality to trends in the prevalence of coronary heart disease in the UK: 1996 –2005. Eur Heart J 2007;28:2142–7. 2. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980 –2000. N Engl J Med 2007;356: 2388 –98. 3. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69 –171. 4. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297: 1197–206. 5. Gibbons RJ. Leading the elephant out of the corner: the future of health care: presidential address at the American Heart Association 2006 Scientific Sessions. Circulation 2007;115:2221–30. 6. Fuster V, Voute J, Hunn M, Smith SC Jr. Low priority of cardiovascular and chronic diseases on the global health agenda: a cause for concern. Circulation 2007;116:1966 –70. 7. Fox KAA, Steg PG, Eagle KA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999 –2006. JAMA 2007;297:1892–900. 8. Fox CS, Coady S, Sorlie PD, et al. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart study. Circulation 2007;115:1544 –50. 9. Hayman LL, Meininger JC, Daniels SR, et al. Primary prevention of cardiovascular disease in nursing practice: focus on children and youth: a scientific statement from the American Heart Association Committee on Atherosclerosis, Hypertension, and Obesity in Youth of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, Council on Epidemiology and Prevention, and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2007;116:344 –57. 10. Balkau B, Deanfield JE, Despres J-P, et al. International Day for the Evaluation of Abdominal Obesity (IDEA): a study of waist circum-
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55
11. 12. 13. 14.
15.
16.
17.
18. 19. 20. 21.
22. 23. 24.
25. 26.
27.
28.
29.
ference, cardiovascular disease, and diabetes mellitus in 168 000 primary care patients in 63 countries. Circulation 2007;116:1942–51. Frieden TR, Bloomberg MR. How to prevent 100 million deaths from tobacco. Lancet 2007;369:1758 – 61. Kallio K, Jokinen E, Raitakari OT, et al. Tobacco smoke exposure is associated with attenuated endothelial function in 11-year-old healthy children. Circulation 2007;115:3205–12. Schroeder SA. Shattuck lecture. We can do better—improving the health of the American people. N Engl J Med 2007;357:1221– 8. Keevil JG, Cullen MW, Gangnon R, McBride PE, Stein JH. Implications of cardiac risk and low-density lipoprotein cholesterol distributions in the United States for the diagnosis and treatment of dyslipidemia: data from National Health and Nutrition Examination Survey 1999 to 2002. Circulation 2007;115:1363–70. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2007;28:2375– 414. World Health Organization. Prevention of cardiovascular disease: pocket guidelines for assessment and management of cardiovascular risk. Available at: http://www.who.int/cardiovascular_diseases/ guidelines/PocketGL.ENGLISH.AFR-D-E.rev1.pdf. Accessed December 19, 2007. Sniderman AD, Holme I, Aastveit A, Furberg C, Walldius G, Jungner I. Relation of age, the apolipoprotein B/apolipoprotein A-I ratio, and the risk of fatal myocardial infarction and implications for the primary prevention of cardiovascular disease. Am J Cardiol 2007;100:217–21. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299 –308. See R, Abdullah SM, McGuire DK, et al. The association of differing measures of overweight and obesity with prevalent atherosclerosis: the Dallas Heart study. J Am Coll Cardiol 2007;50:752–9. Ingelsson E, Sullivan LM, Fox CS, et al. Burden and prognostic importance of subclinical cardiovascular disease in overweight and obese individuals. Circulation 2007;116:375– 84. Pou KM, Massaro JM, Hoffmann U, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart study. Circulation 2007;116:1234 – 41. Gustafson B, Hammarstedt A, Andersson CX, Smith U. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 2007;27:2276 – 83. Halton TL, Willett WC, Liu S, et al. Low-carbohydrate-diet score and the risk of coronary heart disease in women. N Engl J Med 2006;355:1991–2002. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle study (AusDiab). Circulation 2007; 116:151–7. Liu J, Grundy SM, Wang W, et al. Ten-year risk of cardiovascular incidence related to diabetes, prediabetes, and the metabolic syndrome. Am Heart J 2007;153:552– 8. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49: 403–14. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds risk score. JAMA 2007;297:611–9. Guttormsen BN, Stein JH, McBride PE, Cullen MW, Gangnon R, Keevil JG. Rationale for targeted rather than population based screening with C-reactive protein using the National Health and Nutrition Examination Survey (1999 to 2002). Am J Cardiol 2007; 100:1130 –3. Cao JJ, Arnold AM, Manolio TA, et al. Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health study. Circulation 2007;116:32– 8.
Sanz et al. Year in Atherothrombosis
953
30. Lange LA, Carlson CS, Hindorff LA, et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA 2006;296:2703–11. 31. Emberson JR, Ng LL, Armitage J, Bowman L, Parish S, Collins R. N-terminal pro-B-type natriuretic peptide, vascular disease risk, and cholesterol reduction among 20,536 patients in the MRC/BHF Heart Protection study. J Am Coll Cardiol 2007;49:311–9. 32. Olsen MH, Hansen TW, Christensen MK, et al. N-terminal pro-brain natriuretic peptide, but not high sensitivity C-reactive protein, improves cardiovascular risk prediction in the general population. Eur Heart J 2007;28:1374 – 81. 33. Ingelsson E, Pencina MJ, Tofler GH, et al. Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring study. Circulation 2007;116:984 –92. 34. Wilson AM, Kimura E, Harada RK, et al. Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies. Circulation 2007;116:1396 – 403. 35. Wang TJ, Gona P, Larson MG, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 2006;355:2631–9. 36. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GD, Fowkes FG. Relative value of inflammatory, hemostatic, and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery study. Circulation 2007;115:2119 –27. 37. Shantsila E, Watson T, Lip GYH. Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol 2007;49:741–52. 38. Sorrentino SA, Bahlmann FH, Besler C, et al. Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 2007;116:163–73. 39. Levy AP, Purushothaman KR, Levy NS, et al. Downregulation of the hemoglobin scavenger receptor in individuals with diabetes and the Hp 2-2 genotype: implications for the response to intraplaque hemorrhage and plaque vulnerability. Circ Res 2007;101:106 –10. 40. Morgan TM, Krumholz HM, Lifton RP, Spertus JA. Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. JAMA 2007;297:1551– 61. 41. Arnett DK, Baird AE, Barkley RA, et al. Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation 2007;115:2878 –901. 42. Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. N Engl J Med 2007;357:443–53. 43. Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007;316:1341–5. 44. Kathiresan S, Larson MG, Keyes MJ, et al. Assessment by cardiovascular magnetic resonance, electron beam computed tomography, and carotid ultrasonography of the distribution of subclinical atherosclerosis across Framingham risk strata. Am J Cardiol 2007;99: 310 – 4. 45. Kim LG, Scott RAP, Ashton HA, Thompson SG, for the Multicentre Aneurysm Screening Study Group. A sustained mortality benefit from screening for abdominal aortic aneurysm. Ann Intern Med 2007;146:699 –706. 46. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007; 115:459 – 67. 47. Lamina C, Meisinger C, Heid IM, et al. Association of anklebrachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up. Eur Heart J 2006;27:2580 –7. 48. Sen S, Hinderliter A, Sen PK, et al. Aortic arch atheroma progression and recurrent vascular events in patients with stroke or transient ischemic attack. Circulation 2007;116:928 –35. 49. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the
954
50. 51. 52. 53. 54.
55.
56. 57. 58.
59.
60.
61. 62. 63.
64.
65. 66. 67. 68.
69.
Sanz et al. Year in Atherothrombosis American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography). J Am Coll Cardiol 2007;49:378 – 402. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol 2007;49:1860 –70. Rozanski A, Gransar H, Wong ND, et al. Clinical outcomes after both coronary calcium scanning and exercise myocardial perfusion scintigraphy. J Am Coll Cardiol 2007;49:1352– 61. Cassidy-Bushrow AE, Bielak LF, Sheedy PF 2nd, et al. Coronary artery calcification progression is heritable. Circulation 2007;116: 25–31. Hoffmann B, Moebus S, Mohlenkamp S, et al. Residential exposure to traffic is associated with coronary atherosclerosis. Circulation 2007;116:489 –96. Meijboom WB, van Mieghem CAG, Mollet NR, et al. 64-slice computed tomography coronary angiography in patients with high, intermediate, or low pretest probability of significant coronary artery disease. J Am Coll Cardiol 2007;50:1469 –75. Butler J, Shapiro M, Reiber J, et al. Extent and distribution of coronary artery disease: a comparative study of invasive versus noninvasive angiography with computed angiography. Am Heart J 2007;153:378 – 84. Cheruvu PK, Finn AV, Gardner C, et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. J Am Coll Cardiol 2007;50:940 –9. Min JK, Shaw LJ, Devereux RB, et al. Prognostic value of multidetector coronary computed tomographic angiography for prediction of all-cause mortality. J Am Coll Cardiol 2007;50:1161–70. Kim WY, Astrup AS, Stuber M, et al. Subclinical coronary and aortic atherosclerosis detected by magnetic resonance imaging in type 1 diabetes with and without diabetic nephropathy. Circulation 2007; 115:228 –35. Tahara N, Kai H, Yamagishi S, et al. Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. J Am Coll Cardiol 2007;49:1533–9. Rudd JH, Myers KS, Bansilal S, et al. (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trials. J Am Coll Cardiol 2007;50:892– 6. Tahara N, Kai H, Ishibashi M, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2006;48:1825–31. Nicholls SJ, Tuzcu EM, Wolski K, et al. Coronary artery calcification and changes in atheroma burden in response to established medical therapies. J Am Coll Cardiol 2007;49:263–70. Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007;50:933–9. Amirbekian V, Lipinski MJ, Briley-Saebo KC, et al. Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI. Proc Natl Acad Sci U S A 2007;104: 961– 6. Hyafil F, Cornily JC, Feig JE, et al. Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nat Med 2007;13:636 – 41. Kaufmann BA, Sanders JM, Davis C, et al. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation 2007;116:276 – 84. Flaumenhaft R, Tanaka E, Graham GJ, et al. Localization and quantification of platelet-rich thrombi in large blood vessels with near-infrared fluorescence imaging. Circulation 2007;115:84 –93. Niinikoski H, Lagstrom H, Jokinen E, et al. Impact of repeated dietary counseling between infancy and 14 years of age on dietary intakes and serum lipids and lipoproteins: the STRIP study. Circulation 2007;116:1032– 40. Hu G, Tuomilehto J, Borodulin K, Jousilahti P. The joint associations of occupational, commuting, and leisure-time physical activity, and the Framingham risk score on the 10-year risk of coronary heart disease. Eur Heart J 2007;28:492– 8.
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55 70. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503–16. 71. Kereiakes DJ, Teirstein PS, Sarembock IJ, et al. The truth and consequences of the COURAGE trial. J Am Coll Cardiol 2007;50: 1598 – 603. 72. Hueb W, Lopes NH, Gersh BJ, et al. Five-year follow-up of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease. Circulation 2007;115:1082–9. 73. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA 2007;297:177– 86. 74. Wood DA. Clinical reality of coronary prevention in Europe: a comparison of EUROASPIRE I, II and III surveys. Available at: http://www.cardiosource.com/rapidnewssummaries/index.asp?EID⫽ 27&DoW⫽Sun&SumID⫽216. Accessed December 19, 2007. 75. Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med 2007;357:1477– 86. 76. Crouse JR 3rd, Raichlen JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR trial. JAMA 2007; 297:1344 –53. 77. Leeper NJ, Ardehali R, deGoma EM, Heidenreich PA. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation 2007;116:613– 8. 78. Afilalo J, Majdan AA, Eisenberg MJ. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials. Heart 2007;93:914 – 21. 79. Chan PS, Nallamothu BK, Gurm HS, Hayward RA, Vijan S. Incremental benefit and cost-effectiveness of high-dose statin therapy in high-risk patients with coronary artery disease. Circulation 2007; 115:2398 – 409. 80. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499 –508. 81. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301–10. 82. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357: 2109 –22. 83. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;356:1620 –30. 84. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007;370:153– 60. 85. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356: 1304 –16. 86. Tardif JC, Gregoire J, L’Allier PL, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675– 82. 87. Ibanez B, Vilahur G, Cimmino G, et al. Rapid change in plaque size, composition and molecular footprint following recombinant ApoAIMilano (ETC-216) administration. J Am Coll Cardiol 2008. In press. 88. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49: 1982– 8. 89. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. 90. Mehta SR, Granger CB, Eikelboom JW, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol 2007;50:1742–51. 91. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203–16.
JACC Vol. 51, No. 9, 2008 March 4, 2008:944–55 92. Anand S, Yusuf S, Xie C, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007;357:217–27. 93. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. 94. Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007;356:2522– 4. 95. Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med 2007;147:578 – 81. 96. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189 –95. 97. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med 2007;357:28 –38.
Sanz et al. Year in Atherothrombosis
955
98. Rosen CJ. The rosiglitazone story—lessons from an FDA advisory committee meeting. N Engl J Med 2007;357:844 – 6. 99. Food and Drug Administration. Information for Healthcare Professionals. Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl). Available at: http://www.fda.gov/cder/drug/InfoSheets/ HCP/rosiglitazone200707HCP.htm#2007_5. Accessed December 19, 2007. 100. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007;298:1180 – 8. 101. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370: 829 – 40.