YEAR IN CARDIOLOGY SERIES
The Year in Atherothrombosis
Javier Sanz, MD,
Pedro R. Moreno, MD and
Valentin Fuster, MD, PhD*
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 17, 2008;
accepted December 18, 2008.
* Reprint requests and correspondence: Dr. Valentin Fuster, Cardiovascular Institute, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, New York 10029 (Email: valentin.fuster{at}mssm.edu).
Key Words: atherosclerosis • thrombosis • imaging • risk factors • vasculature
Our objective in this paper is to address the most important advances in the last year as they pertain directly to the atherothrombotic process, including those in epidemiology and public health, mechanisms of disease, prevention, early detection and risk stratification, and treatment.
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Epidemiology and Public Health Impact
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The trends in risk factor control in industrialized regions between 1998 and 2006 were evaluated in more than 100,000 patients from the U.S. and 4 European countries. Although there were modest improvements, large proportions of patients remained undertreated, particularly those with the highest risk (1). This included subjects with extracardiac atherosclerosis, as highlighted in a series of patients with peripheral arterial disease who experienced worse long-term outcomes and received fewer secondary prevention therapies than matched patients with coronary heart disease (CHD) (2). Addressing potential sex differences in risk, the INTERHEART study suggested that the same 9 modifiable factors are associated with myocardial infarction (MI) both in men and women worldwide, and that the younger age at presentation in men may be largely related to different risk factor exposure (3). Data from the U.S. indicated that progress in hypertension control has been largely restricted to men; uncontrolled hypertension has become more prevalent in women, particularly at older ages (Fig. 1) (4). Moreover, the Global Burden of Disease 2000 study showed that approximately one-half of the burden of stroke and CHD worldwide is attributable to hypertension or pre-hypertension and that 80% occurs in low- and middle-income countries (5).
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Figure 1 Trends in Hypertension Control in Older American Adults
Age-standardized prevalence (in percentage) of uncontrolled hypertension for  60-year-old men and women in the U.S. in 2 different time periods: 1988 to 1992 and 2001 to 2003. Hypertension control has decreased in women over the studied period. Reprinted, with permission, from Ezzati et al. (4).
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Better risk factor control has translated into global decreases in age-adjusted mortality for CHD. However, data from the U.S. caused concern by showing a paradoxical leveling or even an increase in mortality for 35- to 44-year-old individuals, probably reflecting worsened risk profiles in the young (6). A collective analysis of 3 prospective cohorts from different countries confirmed that dyslipidemia in children predicts abnormal lipid concentrations in adulthood (7). Analogous findings regarding the association between elevated childhood blood pressure and hypertension later in life were reported in a meta-analysis of 50 cohort studies (8). Similarly, childhood body mass index (BMI) (Fig. 2) proved to be a predictor of later CHD (9). Recent data from the National Health and Nutrition Examination Survey showed no significant changes in the prevalence of high BMI in U.S. children and adolescents between 1999 and 2006 (10). However, a study from Finland indicated that type 1 diabetes mellitus in children has doubled over the past 25 years, a change intimately related to obesity (11).
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Figure 2 Obesity in Children and Risk of Future Disease
Association between childhood body mass index (BMI) and the risk of coronary heart disease in adulthood for boys (A) and girls (B). Increased risks are expressed as hazard ratios and 95% confidence intervals for a 1-U increase in BMI z score (the z score is calculated as the difference between every child's BMI and the reference BMI, divided by the standard deviation of the reference population). Note that risk is higher as the child's age increases. Reprinted, with permission, from Baker et al. (9).
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Mechanisms of Disease
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Reduced shear stress, which occurs preferentially at vessel bifurcations, is known to favor plaque formation. An evaluation of extracellular matrix structure using 2-photon excitation microscopy revealed a nearly confluent elastin surface layer along the vessel wall except at branching points, where dense collagen-proteoglycan complexes were exposed, contributing to low-density lipoprotein (LDL) cholesterol retention (12). In another experimental study that performed serial coronary intravascular ultrasound (IVUS) and histopathologic analysis, it was shown that low shear stress is also associated with development of high-risk plaque features such as inflammation, thin fibrous cap, ruptured internal elastic lamina, or eccentric remodeling (13). Conversely, localized high shear stress was identified in regions of plaque rupture in patients with acute coronary syndromes (Fig. 3) (14). Demonstration of increased osteocalcin expression by endothelial progenitor cells in patients with CHD suggested a role for these cells in human vascular calcification (15). Also, an elegant study in apolipoprotein E-deficient mice provided direct quantitative evidence of the role of bone marrow-derived endothelial progenitor cells in the endothelial repair of atherosclerotic lesions with a high cellular turnover (16).
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Figure 3 In Vivo Quantification of Coronary Shear Stress
(A) Longitudinal and cross-sectional images from a 3-dimensional coronary intravascular ultrasound, demonstrating a ruptured plaque (yellow asterisk) in a patient with unstable angina. (B) Corresponding color map of in vivo shear stress distribution, derived through computational fluid dynamics analysis. An area of localized high shear stress (red circle) is noted at the level of the rupture. Reprinted, with permission, from Fukumoto et al. (14).
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Plaque neovascularization is a marker of vulnerability, but its determinants are incompletely understood. A study in human carotid specimens demonstrated the presence of intraplaque hypoxia that, in turn, correlated with neovessel density and enhanced expression of hypoxia-inducible factor, a mediator that stimulates, among other things, the synthesis of vascular endothelial growth factor (17). In addition, a potential role of tissue factor-containing microparticles released from apoptotic macrophages as a stimulus for neovascularization was also described (18). Immature neovascularization favors intraplaque hemorrhage and the release of hemoglobin-bound iron that contributes to plaque growth and destabilization. Homozygosis for the haptoglobin 2 gene was shown to cause impaired clearance of hemoglobin, as demonstrated by increased plaque iron accumulation, which may explain the higher risk associated with this genotype, particularly in patients with diabetes (19).
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Early Detection and Risk Stratification
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Conventional risk factors.
Data from the INTERHEART study further characterized the relationship between dyslipidemia and likelihood of a first MI, and proposed the nonfasting apolipoprotein B/A1 ratio as the best lipid-based predictor regardless of age, sex, or ethnic group (20). These findings were confirmed in a post hoc analysis of 2 large statin trials in patients with established CHD (21). Similarly, the ratio of total to high-density lipoprotein (HDL) cholesterol had a better discriminative power than individual total, LDL, HDL, or non-HDL cholesterol measures for the prediction of fatal CHD in a meta-analysis of 61 prospective observational studies including almost 900,000 apparently healthy adults. Interestingly, lipid parameters were not associated with mortality secondary to stroke (22). The inverse relationship between HDL cholesterol and coronary risk, confirmed in the same meta-analysis, persisted even for markedly reduced LDL cholesterol (<60 mg/dl) in a separate publication (23).
That outcomes are impaired to a similar degree in individuals with diabetes requiring glucose-lowering therapy as in patients without diabetes with a previous MI was confirmed in a population study that followed more than 3 million individuals for 5 years (24). Moreover, a Finnish investigation demonstrated that the trends for reduced CHD incidence and mortality noted in past decades are largely restricted to nondiabetic individuals (25). Regarding other metabolic abnormalities, a combined analysis of 2 large prospective trials in elderly individuals suggested that the presence of the metabolic syndrome may be a better predictor of incident diabetes than of cardiovascular disease (26).
Obesity was one of the risk factors that received closer attention in 2008. Long-term (approximately 24 years) follow-up of the Framingham Offspring study unveiled an independent association between BMI and risk of a first cardiovascular event, even after adjustment for other factors commonly accompanying obesity such as hypertension, diabetes, or dyslipidemia (27). Obesity was also shown to strengthen the association between hypertension and cardiovascular risk in a cohort of more than 1,000,000 men (28). Moreover, waist circumference and waist-to-hip ratio were independently related to the presence of abdominal aortic aneurysms in men (29).
Many common scores for cardiovascular risk stratification estimate the likelihood of developing CHD or a fatal atherosclerotic event. In 2008, novel algorithms were proposed to predict fatal and nonfatal events, including stroke, peripheral arterial disease, or heart failure. These models are based on age, sex, systolic blood pressure, treatment for hypertension, smoking, diabetes, and lipid measures such as total and/or HDL cholesterol (30,31). Importantly, algorithms that do not require laboratory-based tests, and in which cholesterol quantification is replaced by the BMI, were simultaneously developed (30,31). Such simplified, affordable approaches may be particularly useful in resource-poor regions.
Ankle-brachial index (ABI) and biomarkers.
A meta-analysis of 16 prospective studies including more than 48,000 individuals provided justification for routine quantification of the ABI in clinical practice (Fig. 4). In comparison with the normal value (1.1 to 1.4), a low ABI (0.90) doubled or tripled cardiovascular risk after adjusting for the Framingham risk score. Furthermore, inclusion of the ABI in stratification resulted in substantial reclassification of risk category (32).
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Figure 4 Ankle-Brachial Index and Mortality
Unadjusted hazard ratios for total mortality for both men and women as a function of the ankle-brachial index. Reprinted, with permission, from Fowkes et al. (32).
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Increased circulating oxidized LDL levels were associated with future metabolic syndrome after multivariate adjustment in individuals between ages 18 and 30 years followed prospectively for 20 years (33). Conversely, high concentrations of interleukin-5 correlated with reduced carotid intima-media thickness (CIMT), probably through the induction of antibodies against oxidized LDL (34). In contrast to previous series, a large prospective study in more than 11,000 men pointed toward an independent contribution of low testosterone levels to cardiovascular mortality (35). Reinforcing the link between kidney disease and atherothrombosis, a substudy in patients with stable CHD and preserved systolic function demonstrated that albuminuria (even below the threshold of abnormality) predicted all-cause and cardiovascular mortality after accounting for other risk factors and glomerular filtration rate (36). Detection of subclinical myocardial damage was addressed in another investigation in the elderly that quantified plasma troponin I with a high-sensitivity assay, the CIMT and cardiac function with ultrasound and myocardial scar with magnetic resonance imaging (MRI). In multivariate analysis, only male sex, ischemic electrocardiographic changes, and elevated N-terminal pro-brain natriuretic peptide levels, but not myocardial scarring, were associated with increased troponin T concentrations (37).
Several reports addressed the use of serum markers specifically in noncardiac atherothrombosis. In patients with ischemic stroke, elevated levels of prothrombin fragment F 1.2 (an indicator of thrombin generation) were associated not only with large aortic plaques on transesophageal echocardiography but also with recurrent events, suggesting a potential contribution of a hypercoagulable state to the development of stroke in the presence of severe aortic atherosclerosis (38). Similarly, systemic inflammation, as evidenced by high levels of C-reactive protein (CRP), serum amyloid A, and interleukin-6, may play an important role in the pathogenesis of stroke after an acute coronary syndrome (39). In patients with peripheral arterial disease, increased concentrations of CRP, serum amyloid A, and D-dimer predicted decreased survival during the first 2 years after quantification (40).
Regarding risk stratification algorithms, a Reynolds Risk Score that includes plasma concentrations of CRP (and parental history of MI) was proposed for risk stratification in men as previously described in women (41). Additionally, a study in 1,135 elderly men with and without cardiovascular disease described incremental prognostic value for the quantification of CRP, N-terminal pro-brain natriuretic peptide, troponin I, and cystatin C combined. The risk of cardiovascular mortality in patients with elevated concentrations of 2, 3, or 4 biomarkers was increased by a factor of 3, 7, and 17, respectively (42).
Genetics.
The role of recent genome-wide association studies in understanding the contribution of genetic variants to atherothrombosis, diabetes, or dyslipidemias was elegantly reviewed elsewhere (43). Several investigations evaluated the significance of genetic polymorphisms associated with risk factors and their influence on event rates. In a cohort of patients mostly free of cardiovascular disease, a genotype score based on the number of alleles associated with higher LDL or lower HDL cholesterol at 9 genetic loci independently predicted incident events, even after adjustment for other covariates, including baseline lipid levels (44). Polymorphisms of the paraoxonase-1 gene, an enzyme that influences the antioxidant and anti-inflammatory actions of HDL, were also independent predictors in multiadjusted models that controlled for HDL levels or statin use (45). In contrast, loss-of-function mutations of the adenosine triphosphate-binding cassette transporter A1, involved in HDL-mediated reverse cholesterol transport, were not associated with increased CHD in 3 large studies (46). Combined data from 4 large independent studies showed that 4 specific mutations of the CRP gene do not portend increased cardiovascular risk despite being associated with higher plasma CRP concentrations (47).
Invasive imaging.
In the field of IVUS, the influence of diabetes on coronary atherosclerosis was revisited in a pooled analysis of 5 trials that concluded that diabetes is independently associated with higher atheroma burden, faster plaque progression, and possibly inadequate remodeling (48). A virtual histology 3-vessel IVUS evaluation of patients with unstable and stable CHD demonstrated a higher frequency of thin-cap fibroatheromata in the former (average of 2.5 vs. 1.7 lesions per patient, respectively) that were similarly distributed in the proximal 4 cm of the coronary arteries (49). Similar findings were reported using optical coherence tomography, which also revealed other signs of plaque instability (Fig. 5) (50). Additionally, 1 study combined coronary IVUS and optical coherence tomography to demonstrate in vivo the association of positive plaque remodeling with 3 features of vulnerability: a lipid-rich core, a thin fibrous cap, and high macrophage density (51).
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Figure 5 Optical Coherence Tomography of Vulnerable Plaques
Optical coherence tomography images of vulnerable/unstable plaques. (A) Lipid-rich plaque (L) covered by a thin fibrous cap (arrowheads). (B) Magnification of the thin fibrous cap (arrows) and lipid core (L). (C) Example of plaque rupture as a cavity communicating with the lumen, with an overlying fibrous cap fragment (arrows). (D) Example of an irregular thrombus protruding into the lumen (arrowheads). Modified, with permission, from Fujii et al. (50).
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Noninvasive imaging.
The powerful prognostic implications of coronary calcification in different ethnic groups were confirmed in 6,722 asymptomatic participants undergoing computed tomography (CT) in MESA (Multi-Ethnic Study of Atherosclerosis). After adjustment for conventional risk factors, the likelihood of coronary events during a median follow-up of 3.4 years was almost 10 times higher in subjects with an Agatston calcium score >300 in comparison with those with absent calcification (Fig. 6) (52). Data from MESA also indicated that the coronary calcium score is a stronger predictor of events than the CIMT. The adjusted hazard ratios of incident CHD for each increment in 1 standard deviation of maximum CIMT or log-transformed calcium score were 1.2 and 2.5, respectively (53). The role of quantifying coronary calcium in diabetes was prospectively addressed in an investigation of 589 patients with type 2 diabetes in whom the calcium score added prognostic information beyond conventional risk stratification and multiple serum markers (54).
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Figure 6 Association Between Coronary Calcification and Events
Unadjusted survival curves for incident coronary events according to the coronary calcium score in the MESA (Multi-Ethnic Study of Atherosclerosis) study. Reprinted, with permission, from Detrano et al. (52).
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Another application intensively explored during 2008 was the evaluation of noncalcified coronary atherosclerosis with CT angiography. A study in 295 symptomatic patients identified proximal coronary plaque (noncalcified in one-third of the cases) in 44% and 75% of low- and intermediate-Framingham risk patients, respectively, many without current indication for statin therapy (55). The potential prognostic value of CT angiography was highlighted in series of 2,538 consecutive patients followed for an average of 6.5 years. Triple-vessel nonobstructive coronary atherosclerosis was independently associated with mortality and, interestingly, the calcium score still provided additive value to the semi-quantitative information derived from the CT angiography (56). On the other hand, the use of CT angiography as a screening modality in asymptomatic individuals seems unjustified based on another study including 1,000 individuals (57).
Moving outside of the coronary circulation, an MRI study of the carotid circulation demonstrated complex plaques (those with hemorrhage/thrombosis, cap disruption, or calcified nodules) in 16% of patients with <50% luminal stenosis and in 37% of patients with moderate narrowing, suggesting that high-risk lesions may be identifiable even in the absence of severe stenosis (58). Using ultrasound, the degree of post-contrast enhancement in human carotid plaques was shown to correlate with the density of neovessels as well as with plaque echolucency, both markers of vulnerability (59). Similar correlations were described after the use of contrast-enhanced MRI in an experimental model of aortic atherosclerosis that additionally provided in vivo evidence of the association between inflammation (as quantified with 18fluorodeoxyglucose positron emission tomography [PET]) and neovascularization (Fig. 7) (60).
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Figure 7 Multimodality Imaging of Plaque Neovascularization and Inflammation
Multimodality imaging of plaque neovascularization and inflammation in experimental atherosclerosis in rabbits. (A) Color-coded map derived from the area under the signal intensity versus time curve with magnetic resonance imaging after contrast administration. The cross section of the aorta (arrow) is magnified in the vignette. (B) Histology section demonstrating CD31 staining for neovessels (arrow). (C) Positron emission tomographic image of 18fluorodeoxyglucose uptake along the abdominal aorta, with higher localized uptake (red markers). Reprinted, with permission, from Calcagno et al. (60).
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Molecular imaging.
The field of molecular imaging was particularly active in 2008. In a murine model, MRI and iron-oxide particles conjugated to an antibody with high specificity for platelet integrin GPIIb/IIIa were used to monitor clot formation and lysis (61). Another contrast agent containing a gadolinium chelate and a matrix metalloproteinase inhibitor successfully identified metalloproteinase-rich plaques in experimental atherosclerosis (62). Although conventional MRI relies on the detection of hydrogen protons, alternative nuclei can generate MRI-detectable signal. Mice with experimental MI were administered 19F (normally absent in the body) in the form of perfluorocarbon nanoparticles that are phagocytized by macrophages. This approach enabled assessment of infarct inflammatory activity with impressive contrast-to-noise ratios (63). Similarly, monocyte recruitment into murine aortic plaques could be monitored for up to 10 days using serial micro single photon emission computed tomography (SPECT)/CT imaging after administration of exogenous 111In-labeled monocytes (64). 99mTc-labeled annexin A5 imaged with SPECT/CT allowed for in vivo evaluation of the efficacy of novel caspase inhibitors as therapeutic agents to reduce foam cell apoptosis (65). Moving into humans, 18fluorodeoxyglucose PET was used to quantify inflammatory activity in peripheral atherosclerosis (Fig. 8) (66).
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Figure 8 PET-CT Imaging of Peripheral Arterial Inflammation
(Left) Coronal CT image; (middle) PET image; (right) fused PET-CT image. There is marked 18fluorodeoxyglucose accumulation in both superficial femoral arteries (arrows). CT = computed tomography; L = left; PET = positron emission tomography; R = right. Reprinted, with permission, from Rudd et al. (66).
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In addition, novel contrast agents designed for multimodality imaging were developed. A study in mice demonstrated that atherosclerotic lesions could be visualized with MRI using autofluorescent gadolinium-loaded micelles specific to oxidized LDL, which colocalized with plaque macrophages on confocal fluorescence microscopy (67). Another investigation reported the feasibility of detecting macrophage-rich lesions with an iron-based magnetofluorescent nanoparticle additionally labeled with 64Cu, suitable for imaging with PET, MRI, and optical techniques (68).
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Prevention and Treatment
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The importance of primary and secondary cardiovascular prevention was reinforced in 2008. Even modest advances in risk factor control were associated with large reductions in disease incidence in a 25-year follow-up (69). Simulation models from the National Health and Nutrition Examination Survey estimated that MIs and strokes in the U.S. would be respectively reduced by 63% and 31%, respectively, over the next 30 years if all currently recommended preventive measures were implemented, although a staggering 78% of adults would require at least 1 intervention (70). Even further reductions were foreseen if such efforts extended to younger individuals (71). Highlighting the influence of lifestyle choices on risk, the INTERHEART study revealed that a diet rich in vegetables and fruit was associated with a reduction in MI probability of up to 34% (72). The relevance of aggressive medical management in patients with established CHD was also highlighted by the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial: the addition of percutaneous intervention to optimized medical therapy modestly improved quality of life during the first 1 to 2 years, but these differences were lost by the third year (73). Moreover, a multidrug regimen of a statin, aspirin, and 2 blood pressure medications for high-risk individuals in low- and middle-income countries was projected to prevent approximately 20% of cardiovascular deaths over the next 10 years (74).
Alternative approaches for improved prevention were tested in 2008. Encouraging results were reported from EUROACTION, a multinational trial conducted in hospitals and general practices and that randomized more than 5,000 patients with established CHD or high risk to multidisciplinary intervention or usual care. The multidisciplinary intervention program resulted in healthier lifestyle choices and significant improvements in risk factor control after 1 year (75). A similar approach led not only to superior secondary prevention implementation but also to modest decreases in 3-year event rates in post-MI survivors (76). The importance of population-targeted preventive measures was highlighted in a report that demonstrated significant reductions in the incidence of acute coronary syndromes after legislation banning indoor smoking (77).
Lipid therapy.
Intensive statin therapy with rosuvastatin 40 mg/day for 2 years was previously shown to cause coronary plaque regression. A secondary analysis demonstrated concomitant reductions in luminal stenosis (average change: –1.3%) and minimal diameter (average change: –0.03 mm) by quantitative coronary angiography in segments with >25% stenosis at baseline (78). A post hoc analysis of statin-naïve patients enrolled in the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) trial suggested that the benefit of intensive statin therapy is larger with higher levels of baseline LDL and is lost for patients with LDL levels <66 mg/dl (79). Two additional publications provided indirect support for a more widespread use of statins in high-risk subgroups: patients with diabetes (80) and patients with chronic kidney disease (81).
One of the highlights of the year was the publication of the JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin) trial (82). JUPITER randomized 17,802 apparently healthy 50-year-old men and 60-year-old women with LDL cholesterol <130 mg/dl (median: 108 mg/dl) and CRP levels 2 mg/l (median: 4.3 mg/l) to rosuvastatin 20 mg/day or placebo. The trial was stopped prematurely after a median follow-up of 1.9 years because of large and highly significant reductions in both the primary and secondary end points in the rosuvastatin group (Table 1). Therapy with rosuvastatin reduced LDL concentrations by 50% and CRP levels by 37%; which of these is mainly responsible for the observed benefits remains a question.
Ezetimibe (10 mg/day) was compared with placebo in 720 patients with familial hypercholesterolemia also receiving simvastatin 80 mg/day in the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial. Combined therapy for 24 months significantly reduced LDL cholesterol levels (141 ± 53 mg/dl vs. 193.7 ± 60.3 mg/dl; p < 0.01) but did not change the rate of disease progression as measured by the CIMT, the primary end point of the trial (83). It will be necessary to wait for completion of the ongoing IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study to evaluate whether ezetimibe modifies clinical outcomes. Regarding HDL-raising drugs, the peroxisome proliferator activated receptor-alpha agonist bezafibrate was associated with sustained reductions in cardiovascular risk in patients with established CHD, although only in patients not receiving other lipid-lowering therapies (84). Moreover, it was suggested that the protective effects of pioglitazone may be mediated by its ability to raise HDL concentrations (85).
Antihypertensive therapy.
The benefits of treating hypertension even at advanced ages were demonstrated in the HYVET (Hypertension in the Very Elderly Trial). This multinational study randomized 3,845 80-year-old patients with systolic blood pressure 160 mm Hg to placebo or sustained-release indapamide (± perindopril) to a target blood pressure of 150/80 mm Hg. In the intention-to-treat analysis, the primary end point (incident fatal or nonfatal stroke) was reduced by 30% (p = 0.06), and there were significant reductions in death from stroke (39%), death from any cause (21%), and heart failure (64%) (86). However, a prospective cohort of almost 170,000 Chinese individuals indicated that treated and controlled hypertension still carries a higher cardiovascular risk than normotensive status, emphasizing the importance of primary prevention (87).
Therapy for diabetes.
Robust evidence on the importance of aggressive medical management in patients with diabetes became available in 2008. A regimen of intensive glucose control to a target glycated hemoglobin value  6.5% was compared with standard care in 11,140 type 2 diabetic patients in the randomized ADVANCE (Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial. After a median follow-up of 5 years, there was a significant 10% reduction in the combined outcome of major macrovascular and microvascular complications, although mainly restricted to microvascular events (88). Longer follow-up was available in the UKPDS (United Kingdom Prospective Diabetes Study) trial, in which patients with newly diagnosed type 2 diabetes were randomized to conventional glucose control (diet) or to intensive therapy with sulfonilureas and insulin (or, for overweight patients, metformin). After the conclusion of the trial, 3,277 patients were followed for up to 10 additional years. Among different improvements, some only apparent during the post-trial period, the intensive therapy arm experienced significant decreases in total mortality and incident MI. These reductions were particularly substantial in the metformin group (Fig. 9) (89). A smaller study randomized 160 type 2 diabetic patients with microalbuminuria to conventional or intensive medical therapy for an average of 7.8 years, with an additional observational follow-up of 5.5 years. The intensive approach (which included stricter metabolic and blood pressure targets, behavioral modification, renin-angiotensin blockers, lipid-lowering drugs, and aspirin) halved the risk of overall mortality (hazard ratio: 0.54; p = 0.02) and cardiovascular events (hazard ratio: 0.41; p < 0.001) (90). Moreover, a study in 499 American Indian individuals with type 2 diabetes suggested that lower targets of systolic blood pressure and LDL cholesterol (115 mm Hg and 70 mg/dl, respectively) may be appropriate for these patients. The study did not find differences in events in the limited 3-year follow-up period, but reported regression of CIMT in the intensive arm (91). In an additional imaging investigation, pioglitazone was associated with slower progression of IVUS-based atheroma than was glimepiride (92).
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Figure 9 Glucose Control in Diabetes and Prognosis
Comparisons between the intensive versus conventional glucose control arms of the UKPDS (United Kingdom Prospective Diabetes Study) trial with regard to the cumulative incidence of myocardial infarction (A and B) and mortality (C and D). Modified, with permission, from Holman et al. (89).
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Antiplatelet therapy.
Current guidelines recommend the temporary addition of clopidogrel to aspirin after an acute coronary syndrome. A retrospective analysis raised concerns of a potential rebound effect associated with the interruption of clopidogrel, with subsequent 90-day clustering of death and MI both in patients treated medically and in those receiving stents (93). Also addressing dual antiplatelet therapy in secondary prevention, aspirin plus extended-release dipyridamole or clopidogrel alone were similarly efficacious in reducing the risk of recurrent stroke or the composite of stroke, MI, or vascular death among 20,332 patients with a previous noncardioembolic ischemic stroke. However, the combination therapy resulted in a 15% increase in the risk of major bleeding (94).
In addition, several studies addressed the hypercoagulable state associated with diabetes and its influence on antithrombotic therapy. A trial in 2,539 Japanese individuals with type 2 diabetes evaluated the use of low-dose aspirin for cardiovascular primary prevention. After a median follow-up of 4.4 years, aspirin did not reduce global atherosclerotic events, the primary end point of the trial, but suggested a potential benefit in the risk of fatal coronary or cerebrovascular events (95). A subanalysis of the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) trial compared clopidogrel and prasugrel in 3,146 diabetic patients with an acute coronary syndrome. The prasugrel arm experienced a significant 14% reduction in the primary efficacy end point (Fig. 10) without the increased rates of bleeding found in nondiabetic subjects (96). Moreover, a post hoc analysis of the complete trial population demonstrated that prasugrel reduced not only first but also subsequent events during follow-up (97).
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Figure 10 Benefits of Prasugrel in Diabetic Atherothrombosis
Rates of the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) trial according to diabetic status. The benefits of more potent antiaggregation with prasugrel are particularly evident in diabetic patients. DM = diabetes mellitus; HR = hazard ratio. Modified, with permission, from Wiviott et al. (96).
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Other therapies.
Additional data on the benefits associated with blocking the renin-angiotensin system in high-risk patients came from the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) study, which randomized patients with established cardiovascular disease or diabetes with end-organ damage to ramipril, telmisartan, or the combination. After a median follow-up of almost 5 years, the combination of cardiovascular death, MI, stroke, or hospitalization for heart failure occurred in 16.5%, 16.7%, and 16.3% of each arm, respectively. It was concluded that telmisartan was as efficacious as ramipril for prevention of events; the combination did not provide additional benefits despite a greater reduction in blood pressure (98).
Darapladib, a novel oral lipoprotein-associated phospholipase A2 inhibitor, was compared with placebo in a study of 330 CHD patients who underwent coronary IVUS at baseline and at 12 months. The change in atheroma volume was similar between groups, but darapladib was associated with no change in necrotic core size whereas the placebo arm experienced an increase (–0.5 ± 13.9 mm3 vs. 4.5 ± 17.9 mm3; p < 0.01) (99). Succinobucol, a novel antioxidant drug, was compared with placebo in patients with previous acute coronary syndrome. Succinobucol did not affect the 2-year rate of the primary end point although it reduced the incidence of the combination of cardiovascular death, cardiac arrest, MI, or stroke (100). Finally, another IVUS investigation evaluated the effect on coronary plaque burden of rimonobant, which caused reductions in total but not percent atheroma volume after 18 months of therapy (101).
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Conclusions
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The year 2008 brought numerous advances in our understanding of atherothrombosis. The use of imaging modalities, the importance of intensive medical therapy and risk factor control (especially in diabetic patients), and novel indications for statin therapy constituted the highlights of a productive year.
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Acknowledgments
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The authors express appreciation to Dr. Boris Vesga for his collaboration in data acquisition for this paper.
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References
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