Coronary Artery Atherosclerosis Treatment & Management
- Author: F Brian Boudi, MD, FACP; Chief Editor: Yasmine Subhi Ali, MD, FACC, FACP, MSCI more...
The treatment goals for patients with coronary artery atherosclerosis are to relieve symptoms of coronary artery disease (CAD) and to prevent future cardiac events, such as unstable angina, AMI, and death.
The mainstays of pharmacologic therapy of angina include nitrates, beta-blockers, statins, calcium-channel blockers, and ranolazine. The prevention and treatment of atherosclerosis requires control of the known modifiable risk factors for this disease. This includes therapeutic lifestyle changes and the medical treatment of hypertension, hyperlipidemia, and diabetes mellitus.
Typically, patients with CAD are first seen after they present with a cardiac event. The main focus of their treatment is the index event. The past 4 decades have witnessed tremendous progress in the areas of acute cardiac care, coronary care unit expansion, thrombolytic usage, and PCI. Nevertheless, prevention of cardiac events is likely to have the largest impact on decreasing the burden of atherosclerosis.
High-risk subgroups, in particular, can be targeted for early intervention. Grover and colleagues showed statin therapy in diabetic patients without CAD to be as cost-effective as statin therapy in nondiabetic patients with CAD. Pharmacotherapeutic strategies that affect the risk factor profile, such as the administration of statins for low-density lipoprotein (LDL) reduction or the administration of agents that alter atherosclerotic plaque, are of paramount importance.
Statin monotherapy vs combination therapy
In a systematic review using data from 36 randomized, controlled trials, Gudzune et al concluded that in patients who cannot tolerate or do not respond to high-intensity statin monotherapy, combination therapy using lower-intensity statin therapy in combination with a bile acid sequestrant or with ezetimibe should be considered, albeit cautiously.[52, 53]
According to the report, in high-risk patients with hyperlipidemia, a combination of low-intensity statin therapy and a bile acid sequestrant produces a 0-14% greater reduction in low-density lipoprotein cholesterol (LDL-C) than does mid-intensity statin monotherapy.[52, 53] Similarly, it was found that compared with high-intensity statin monotherapy, mid-intensity statin therapy combined with ezetimibe results in a 5-15% greater reduction in LDL-C in patients with atherosclerotic cardiovascular disease and a 3-21% greater LDL-C reduction in patients with diabetes.
The investigators urged caution, however, in the use of the above combination therapies, because the trials used in the report lacked data on the long-term benefits and risks of such treatment.[52, 53]
Prevention of future cardiac events
Findings from the World Health Organization's Monitor Trends in Cardiovascular Diseases (MONICA) project involving 21 countries showed a 4% fall in CAD death rates. Improvement in the case fatality rate accounted for only one third of the decline; two thirds of the decline resulted from a reduction in the number of events. These findings strongly suggest that the largest impact on decreasing the global burden of atherosclerosis will come from prevention of events.
Fortunately, the natural history of CAD is characterized by early onset and a long dormant phase. This provides an excellent opportunity to intervene in order to reduce the number and severity of cardiovascular events.
The goals of therapy should include arresting atherosclerosis or even reversing its progression. Large, multicenter randomized trials of various pharmacologic modalities have recently achieved great success in the treatment of patients with coronary artery atherosclerosis. In addition, addressing risk factors with lifestyle changes is an integral part of atherosclerosis prevention.
Therapy with lipid-lowering agents should be a component of multiple risk factor intervention and is indicated in primary prevention as an adjunct to diet therapy when the response to a diet restricted in saturated fat and cholesterol has been inadequate. Substantial evidence supports the use of statins in the secondary prevention of CAD, and the efficacy of statins has recently been extended to include primary prevention of CAD in patients with average cholesterol levels.
Niacin is superior to ezetimibe for combination therapy in high-risk patients being treated with statin monotherapy. However, in an industry-supported study, patients with atherosclerotic cardiovascular disease and LDL-C levels of < 70 mg/dl (1.81 mol/L) experienced no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL-C and triglyceride levels.
A separate study found that, compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. However, further investigation is warranted.
A meta-analysis of nearly 5000 patients found that statins administered before invasive procedures significantly reduced the risk for postprocedural myocardial infarction. The risk for MI was reduced after percutaneous coronary intervention and noncardiac surgical procedures, but not for coronary artery bypass grafting (CABG). Statins decreased the risk for atrial fibrillation following CABG.
Current guidelines recommend using statin therapy after CABG to keep LDL levels below 100 mg/dL. Results of the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial confirmed that this practice independently associated with improved graft patency, as demonstrated by coronary angiography and saphenous vein graft intravascular ultrasonography. performed 12 months postoperatively. However, LDL reduction to less than 70 mg/dL did not lead to further improvement in graft patency.
Statin therapy is also safe and can improve liver tests while reducing cardiovascular morbidity in patients with mild- to moderately-abnormal liver test results that may be attributable to nonalcoholic fatty liver disease.
In the United States, the most commonly used guidelines for cholesterol management are those from the NCEP Adult Treatment Panel (ATP). In high-risk persons, the recommended LDL-C goal is less than 100 mg/dL, but when risk is very high, an LDL-C goal of less than 70 mg/dL is a therapeutic option and a reasonable clinical strategy based on available clinical trial evidence. For moderately high-risk persons (≥2 risk factors and 10-y risk of 10-20%), the recommended LDL-C goal is less than 130 mg/dL, but an LDL-C goal of less than 100 mg/dL is a therapeutic option based on trial evidence.
Newer guidelines on the management of elevated blood cholesterol, released in late 2013 by the American Heart Association/American College of Cardiology (AHA/ACC), no longer specify LDL- and non-HDL-cholesterol targets for the primary and secondary prevention of atherosclerotic cardiovascular disease.[59, 60] The new guidelines identify four groups of primary- and secondary-prevention patients in whom efforts should be focused to reduce cardiovascular disease events and recommend appropriate levels of statin therapy for these groups.
Treatment recommendations include the following :
In patients with atherosclerotic cardiovascular disease, or those with LDL cholesterol levels 190 mg/dL or higher (eg, due to familial hypercholesterolemia), and no contraindications, high-intensity statin therapy should be prescribed to achieve at least a 50% reduction in LDL cholesterol
In patients aged 40 to 75 years of age with diabetes, a moderate-intensity statin that lowers LDL cholesterol by 30% to 49% should be used; in those patients who also have a 10-year risk of atherosclerotic cardiovascular disease exceeding 7.5%, a high-intensity statin is a reasonable choice
In individuals aged 40 to 75 years without cardiovascular disease or diabetes but with a 10-year risk of clinical events >7.5% and an LDL-cholesterol level of 70-189 mg/dL, a moderate- or high-intensity statin should be used
A study applying the 2013 AHA/ACC cholesterol guidelines to data from the 2005–2010 National Health and Nutrition Examination Surveys (NHANES) estimated that an additional 12.8 million US adults would be eligible for statin therapy as compared with treatment based on the NCEP ATP III guidelines.[61, 62] About 10.4 million of these adults would be eligible to receive statins for primary prevention—primarily older people without cardiovascular disease, men more often than women, those with higher blood pressure, and those with lower LDL-C levels.
New AHA/ACC guidelines also recommend use of a revised calculator to estimate the risk of developing a first atherosclerotic cardiovascular disease (ASCVD) event, which is defined as one of the following, over a 10-year period, in a person who was initially free from ASCVD :
Nonfatal myocardial infarction
Death from coronary heart disease
Stroke (fatal or nonfatal)
For patients 20-79 years of age who do not have existing clinical ASCVD, the guidelines recommend assessing clinical risk factors every 4-6 years. For patients with low 10-year risk (< 7.5%), the guidelines recommend assessing 30-year or lifetime risk in patients 20-59 years old.
Regardless of the patient’s age, clinicians should communicate risk data to the patient and refer to the AHA/ACC lifestyle guidelines, which cover diet and physical activity. For patients with elevated 10-year risk, clinicians should communicate risk data and refer to the AHA/ACC guidelines on blood cholesterol and obesity.
Treatment of Low HDL levels and High Triglyceride levels in Patients With Diabetes
A combination of low HDL levels and high triglyceride levels is frequently encountered in patients with diabetes and is often referred to as atherogenic dyslipidemia. Many of these patients have metabolic syndrome.
Additional follow-up and analysis of the Veterans Affairs HDL Intervention Trial (VA-HIT) indicated that treatment with gemfibrozil versus placebo resulted in a 32% reduction in major cardiovascular events and a 41% reduction in CHD deaths, in 769 male subjects with diabetes mellitus and CHD who had HDL-C levels of less than 40 mg/dL and LDL-C levels of less than 140 mg/dL.
Interestingly, among 1733 nondiabetic men, increased plasma fasting insulin levels and insulin resistance, as assessed by the homeostasis model assessment for insulin resistance (HOMA-IR; fasting insulin [µU/mL] X fasting glucose [mmol/L]/22.5), were predictive of increased major cardiovascular events and of greater benefit from gemfibrozil treatment.[63, 64]
Somewhat inexplicable was the finding that despite higher plasma triglyceride and lower HDL-C levels in insulin-resistant subjects, these measurements were associated with greater treatment benefit only in those subjects classified as not having insulin resistance by HOMA-IR.
This was the first trial to demonstrate the cardiovascular benefit of treating diabetic and insulin-resistant subjects with low HDL-C levels. Interestingly, the insulin resistance was more predictive of CHD event rate and benefit from gemfibrozil than were HDL-C or triglyceride levels. Because no significant reduction in LDL-C was realized with gemfibrozil therapy, one possibility is that additional CHD benefit would be accrued by adding statins, which have been shown in subgroup analyses of several trials to benefit CHD risk in diabetic patients and in nondiabetic patients with low HDL-C levels.
One caveat is that because of the relatively higher risk of myopathy with combined gemfibrozil-statin treatment and findings that indicate much less risk with statins and fenofibrate, the latter is currently the preferred choice for combined treatment.
ACE Inhibitors to Reduce Blood Pressure
The efficacy of ACE inhibitors on CAD has been examined in blood pressure reduction studies and in studies of subjects with high risk factors for CAD.
ACE inhibitors are effective blood pressure–reducing agents and affect the heart and vasculature through direct and other mechanisms.
ACE inhibitors were not shown to affect plaque in a randomized angiographic regression study, the Quinapril Ischemic Event Trial (QUIET), of 463 subjects with CAD.
B-mode ultrasonographic studies investigating plaque regression have provided confusing results at best. Although the second Prevention of Atherosclerosis with Ramipril Trial (PART 2) showed no reduction in intima-media thickness at 4-year follow-up in 617 subjects randomized to placebo or ramipril (5-10 mg/d), the Study to Evaluate Carotid Ultrasound Changes with Ramipril and Vitamin E (SECURE) showed a reduction in carotid intima-media thickness proportional to the dose of ramipril (2.5-10 mg/d) in 750 subjects over a 4.5-year follow-up period.
ACE inhibitors probably affect endothelial function, as well as those of A-II and kinin, to elicit the clinical effects observed in the clinical trials. Tissue binding is variable among the ACE inhibitors, with the highest affinity shown by quinapril, benazepril, and ramipril. In the Trial on Reversing Endothelial Dysfunction (TREND), which included 105 subjects with CAD (but without CHF or left ventricular dysfunction), the group receiving quinapril at 40 mg/d showed significantly improved response to acetylcholine. ACE inhibitors also increase levels of nitric oxide by increasing its release through a kinin-mediated pathway and through reduction of its breakdown.
Statin therapy decreases cardiovascular events and all-cause mortality in both women and men.
In addition, ACE inhibitors decrease the plasma levels of type 1 plasminogen activator inhibitor, increase the release of tissue-type plasminogen activator, and favorably affect the fibrinolytic balance, an effect not observed with the angiotensin receptor–blocking agents.
In terms of blood pressure reduction, even though a greater stroke incidence was observed with higher baseline blood pressure in the treatment group in the Captopril Prevention Project (CAPPP), a pooled analysis of 16,161 patients from blood-pressure control trials evaluating ACE inhibitors showed no difference in the cardiovascular outcome risk.
A possible direct effect of ACE inhibitors on atherosclerosis, independent of blood pressure reduction, was suggested by the Heart Outcomes Prevention Evaluation (HOPE) study, which included 9297 subjects with history of CAD, stroke, peripheral vascular disease, or diabetes, along with one other CAD risk factor (eg, hypertension, hypercholesterolemia, hypoalphalipoproteinemia, tobacco abuse, microalbuminuria). Subjects were randomized to placebo or ramipril (10 mg/d). At 5-year follow-up, the cardiac death rate was reduced by 25%, nonfatal MI by 20%, need for bypass surgery/PTCA by 16%, and all-cause mortality by 16%. The effects were unrelated to the blood pressure–lowering effect.
Antiplatelet Agents for Acute Coronary Events
Antiplatelet agents help reduce the number of acute coronary events. Convincing data are available from the following studies:
Antiplatelet Trialists' Collaboration 
Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial 
Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial 
Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes (TRITON TIMI-38) 
The risk of myocardial ischemic events in patients with ACS has been shown to be reduced by means of platelet inhibition with the use of aspirin. Currently, all patients with documented CAD are recommended to be treated with daily aspirin, unless contraindicated. The CAPRIE trial studies the efficacy of clopidogrel (an inhibitor of the P2Y12 adenosine-diphosphate receptor), compared with that of aspirin, on long-term events. Recurrent cardiovascular events were modestly reduced in patients treated with clopidogrel, in comparison with aspirin.
Extending this, the CURE trial found that regardless of the initial treatment strategy (medical therapy, PCI, or CABG), treatment with the combination of aspirin and clopidogrel was superior to aspirin alone in reducing recurrent events for up to 12 months after hospitalization with ACS. However, in the CHARISMA trial, prolonged dual antiplatelet therapy with aspirin and clopidogrel did not significantly reduce recurrent events in patients with stable cardiovascular disease or in asymptomatic patients at high risk for cardiovascular events.
In the TRITON TIMI-38 trial, prasugrel, a more potent thienopyridine P2Y12 inhibitor, proved more effective than clopidogrel in reducing ischemic events, including stent thrombosis, among patients with ACS who were scheduled for percutaneous coronary intervention. However, the risk of major bleeding, including fatal bleeding, was higher with prasugrel (2.4% versus 1.8% with clopidogrel), although overall mortality did not differ significantly between treatment groups.
Low-dose prasugrel may also be effective in very elderly patients. In a pharmacodynamic and pharmacokinetic study involving 155 patients with stable CAD, investigators found that a 5-mg dose of prasugrel provided adequate platelet inhibition in very elderly patients.[75, 76] The study subjects, who were either aged 45-65 years (mean, 56 y) or older than 75 years (mean, 79 y), were treated for 12 days during each of 3 crossover treatment periods with 1 of 3 regimens: clopidogrel 75 mg, prasugrel 5 mg, or prasugrel 10 mg.
Median maximal platelet aggregation (MPA) response to prasugrel 5 mg in very elderly patients (58%) was noninferior to the 75th percentile of MPA response to prasugrel 10 mg in nonelderly patients (52%). Antiplatelet effect was significantly lower and high on-treatment platelet reactivity rates significantly higher with prasugrel 5 mg in very elderly patients than with prasugrel 10 mg in nonelderly patients. Prasugrel 5 mg had significantly greater antiplatelet effect than clopidogrel 75 mg in very elderly patients, as did prasugrel 10 mg in nonelderly patients.
The incidence of bleeding-related adverse events in older patients was similar to that in younger patients. Bleeding rates were similar with prasugrel 5 mg and clopidogrel 75 mg but were significantly higher with prasugrel 10 mg.
ACC/AHA guidelines recommend that after an ACS, all patients should receive dual antiplatelet therapy, ideally for 12 months, followed by lifelong aspirin therapy. The ACCF/ACG/AHA 2010 Expert Consensus provides a detailed report on reducing the GI risks of antiplatelet therapy and NSAID Uuse.
Pharmacologic Treatment of Angina
A number of agents have proven helpful for the treatment of angina. These include beta-blockers, calcium channel blockers, nitrates, and ranolazine (see below).
Beta-blockers inhibit sympathetic stimulation of the heart, reducing heart rate and contractility; this can decrease myocardial oxygen demand and thus prevent or relieve angina in patients with CAD. Since beta-blockers reduce the heart rate–blood pressure product during exercise, the onset of angina or the ischemic threshold during exercise is delayed or avoided. All types of beta-blockers appear to be equally effective in the treatment of exertional angina. The ACC and AHA recommend beta-blockers, unless contraindicated, in all patients with stable angina who have had an ACS or who have left ventricular dysfunction.
Calcium channel blockers
Calcium-channel blockers prevent calcium entry into vascular smooth muscle cells and myocytes, which leads to coronary and peripheral vasodilatation, decreased atrioventricular (AV) conduction, and reduced contractility. In patients with angina, these effects result in decreased coronary vascular resistance and increased coronary blood flow. Calcium blockers also reduce systemic vascular resistance and arterial pressure and provide a negative inotropic effect.
Nitrates are effective in the treatment of acute anginal symptoms. In this situation, they are usually given sublingually. The primary anti-ischemic effect of nitrates is to decrease myocardial oxygen demand by producing systemic vasodilation, although they also cause modest coronary and arteriolar vasodilation, as well as venodilation.
In patients with chronic stable angina, nitrate therapy improves exercise tolerance, time to onset of angina, and ST-segment depression during exercise testing. They are particularly effective in combination with beta-blockers or calcium-channel blockers.
Ranolazine is a novel antianginal agent believed to relieve ischemia by reducing myocardial cellular sodium and calcium overload via inhibition of the late sodium current of the cardiac action potential.
In 3 randomized, double-blind trials of patients with chronic angina, ranolazine prolonged exercise duration and reduced symptoms when given as either monotherapy or in combination with other antianginal drugs. When evaluated in patients with non-ST-elevation ACS, ranolazine reduced recurrent ischemia but did not significantly reduce the risk of death or MI at 1 year.
Hormone Therapy Concerns
Hormone therapy has been found to be more risky than beneficial as a means of protecting postmenopausal women against CAD. The Heart and Estrogen/Progestin Replacement Study follow-up (HERS-II), completed in 2002, reported that after 6.8 years, hormone therapy did not reduce risk of cardiovascular events.
Similarly, in a study by the Women’s Health Initiative, overall health risks exceeded benefits from the use of combined estrogen and progestin therapy as a means of primary prevention of CAD in healthy, postmenopausal women. Participants in the trial were randomized into hormone therapy (n = 8506) or placebo (n = 8102) groups. The average follow-up period was 5.2 years. All-cause mortality in the study was unaffected by the combination therapy.
Because of overall increased risk, combined estrogen and progestin therapy should not be initiated or continued for primary prevention of CAD.
Antibiotic Therapy in Coronary Artery Atherosclerosis
Although inflammation is considered to be a risk factor for the development of atherosclerosis, antibiotic therapy does not appear to have a significant role in secondary prevention of this disorder. Several multicenter trials have evaluated the effect of antibiotic therapy on recurrent cardiac events when used as secondary prevention. The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infarction with Chlamydia (ACADEMIC) trial, the Azithromycin in Acute Coronary Syndrome (AZACS) study, the South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA), the Azithromycin Coronary Events Study (ACES), and the antibiotic arm of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial all returned negative results in terms of any significant benefit from antibiotic therapy.
Revascularization therapies for symptomatic or ischemia-producing atherosclerotic lesions include percutaneous approaches and open heart surgery. For a detailed discussion of these approaches, see Percutaneous Transluminal Coronary Angioplasty and Comparison of Revascularization Procedures in Coronary Artery Disease.
Long-term mortality has been similar after CABG and PCI in most patient subgroups with multivessel CAD; therefore, the choice of treatment typically depends on patient preferences for other outcomes. Exceptions to this are patients with diabetes and those age 65 years or older; Hlatky et al found CABG to be a superior option in these subgroups, because of lower mortality.
The SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) study determined that in high- and intermediate-risk patients with 3-vessel disease, the rates of revascularization and of major adverse cardiac and cerebrovascular events were significantly higher in patients who had undergone PCI than in those who had undergone CABG.[2, 3] The study also found that PCI and CABG were equally effective in the treatment of low-risk patients with 3-vessel disease and in low- and intermediate-risk patients with left main CAD.
In a more recent study that compared the long-term prognostic value of baseline (ss) and clinical SYNTAX scores (cSS) in 460 Turkish patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease who either underwent CABG (n = 214) or PCI (n = 246), investigators found that ss and cSS had prognostic value in the CABG group but not the PCI group. Moreover, in the CABG group, cSS appeared to have more discriminative power than SS for long-term adverse effects.
Other revascularization techniques include transmyocardial laser revascularization.
Medical therapy versus PCI revascularization
The COURAGE trial demonstrated that performing PCI in severe lesions reduces angina but does not improve overall outcomes over medical therapy alone in patients with stable CAD. The trial randomized patients with stable CAD, ischemia, and significant stenoses of 70% or more in at least 1 proximal coronary artery to a regimen of optimal medical treatment alone or optimal medical treatment combined with PCI. The primary outcome was death from any cause or non-fatal MI during a follow-up period of between 2.5 and 7 years (median 4.6 years).
The results of COURAGE showed no evidence of a better outcome for the PCI group than for the group receiving medical treatment alone, for the combined endpoint death, MI and stroke (20.0% PCI group vs 19.5% medical treatment); for admission to hospital for ACS (12.4% vs 11.8%, respectively); or for MI (13.2% vs 12.3%, respectively). Thus, at least among the patients studied in COURAGE, both treatment strategies resulted in similar outcomes for major cardiac complications and deaths. There was a statistically significant advantage for reduction in the prevalence of angina in the PCI group, with respect to freedom from angina. However, by the end of 5 years of follow-up, the difference was no longer significant (74% of the PCI group and 72% of the group receiving medical treatment only were free of angina).
The results of the trial likely resulted from the fact that most of the lesions responsible for later coronary events are nonobstructive. Thus, prophylactic stenting of all identified lesions (the full metal jacket) is impractical and certainly not justified at this time.
In a prospective, natural-history study of coronary atherosclerosis, patients underwent 3-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Major adverse events were related to both recurrence at the site of culprit lesions and to nonculprit lesions.
European Society of Cardiology Guidelines
The European Society of Cardiology (ESC) released updated guidelines on the management of stable CAD.[90, 91] These guidelines note that microvascular angina and vasospasm are more common as causes of angina than previously believed, and they increase reliance on pretest probabilities (PTP) for stable CAD as well as discuss a larger role for modern imaging modalities (eg, cardiac magnetic resonance [CMR] imaging and coronary computed-tomography angiography [CCTA]).
Highlights of these new guidelines include the following[90, 91] :
PTP for a CAD diagnosis uses more contemporary data than those used in the Diamond and Forrester Chest Pain Prediction Rule: For example, in patients with suspected CAD using the new criteria, if the PTP is < 15%, investigate other possible causes and consider a diagnosis of functional coronary disease; if the PTP is intermediate (eg, 15%-85%), send the patient for noninvasive testing; if the PTP is high (eg, >85%), a diagnosis of CAD is established, and patient risk stratification should follow
In stable CAD, the functional impact of coronary lesions relative to their angiographic severity has a larger role than previously in determining the role of PCI
In patients with severe symptoms or clinical characteristics suggestive of high-risk coronary anatomy: Initiate guideline-directed medical therapy
For noncomplex coronary disease: Consider medical therapy first; in the presence of complex coronary lesions or if the patient has many comorbidities, CABG is preferred over PCI; however, if the patient prefers PCI, use drug-eluting stents
In patients within the lower range of intermediate PTP for stable CAD (in whom good image quality can be obtained): Consider CCTA as an alternative to stress-imaging techniques (1) to exclude stable CAD and (2) after an inconclusive exercise electrocardiogram (ECG) or stress imaging test or those in whom stress testing is contraindicated
On first contact in every person with chest pain: Obtain a resting echocardiogram
In patients with a clinically important left main coronary artery stenosis: If there is only 1-vessel involvement, use PCI for ostial or mid-shaft lesions but also include a heart team discussion to decide on PCI or CABG for lesions at a distal bifurcation; for multivessel involvement, use the SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) score (eg, if ≤22, the team should discuss, but if ≥23, CABG should be chosen)
New second-line anti-anginal agents include ranolazine, nicorandil, and ivabradine (not approved for angina in the United States)
However, the following 3 studies are not recommended[90, 91] :
Coronary calcium scoring on CT imaging in asymptomatic patients
Screening for CAD with CCTA in asymptomatic patients
Stenosis quantification with CCTA in patients with a high likelihood of calcifications
In collaboration with the European Association for the Study of Diabetes (EASD), the ESC also developed guidelines on diabetes, prediabetes, and cardiovascular diseases; these guidelines place emphasis on the following[90, 92] :
Less aggressive approach to glycemic control for the elderly and patients with "long-standing diabetes with autonomic neuropathy”
A “simplified diagnostics” algorithm in which glycosylated hemoglobin or fasting plasma glucose studies have priority in the workup, but the oral glucose-tolerance test is reserved for "cases of uncertainty”
CABG as the preferred/first revascularization choice, rather than PCI
High intakes of red or processed meat were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality in a study by Sinha et al. The baseline population was a cohort of half a million people aged 50-71 years from the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study.
A meta-analysis by Ferdowsian and Barnard suggested that plant-based diets are effective in lowering plasma cholesterol concentrations. In a review of 4 types of plant-based diets studied in 27 trials, a vegetarian or vegan diet combined with nuts, soy, and/or fiber demonstrated the greatest effects (up to 35% reduction in plasma LDL-C, followed by vegan and ovolactovegetarian diets. Diets that included small amounts of lean meat demonstrated less dramatic reductions in levels of total cholesterol and LDL.
The ATP III recommended a multifaceted lifestyle approach to reduce the risk for CHD. This is the approach of therapeutic lifestyle changes (TLCs), and its essential features are as follows:
Reduced intake of saturated fats (< 7% of total energy intake) and cholesterol (< 200 mg/d)
Therapeutic options for enhancing LDL lowering, such as plant stanols/sterols (2 g/d) and increased viscous (soluble) fiber intake (10-25 g/d)
Increased physical activity
To initiate TLCs, intake of saturated fats and cholesterol is first reduced to lower LDL-C levels. To improve overall health, the ATP III TLC diet generally contains the recommendations embodied in the Dietary Guidelines for Americans, 2000. One exception is that total fat is allowed to range from 25-35% of total energy intake, provided saturated fats and trans fatty acids are kept low. A higher intake of total fat, mostly in the form of unsaturated fat, can help to reduce triglyceride levels and to raise HDL-C levels in persons with the metabolic syndrome.
In accordance with the Dietary Guidelines, moderate physical activity is encouraged. After 6 weeks, the LDL response is determined; if the LDL-C goal has not been achieved, other therapeutic options for LDL lowering, such as plant stanol/sterols and viscous fiber, can be added.
After maximum reduction of LDL-C levels with dietary therapy, emphasis shifts to management of the metabolic syndrome and associated lipid risk factors. Most persons with these latter abnormalities are overweight or obese and sedentary.
Weight therapy for patients who are overweight or obese enhances LDL lowering and provides other health benefits, including modification of other lipid and nonlipid risk factors. Assistance in the treatment of these patients is provided by the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults from the NHLBI Obesity Education Initiative (1998). Additional risk reduction can be achieved by simultaneously increasing physical activity.
At all stages of dietary therapy, physicians are encouraged to refer patients to registered dietitians or other qualified nutritionists for medical nutrition therapy, which is the term for the nutritional intervention and guidance provided by a nutrition professional.
Moderate alcohol intake (20 g/day or less) in men is associated with a reduced incidence of coronary heart disease events. The mechanism(s) of this benefit is not well understood. Although alcohol may have cardiovascular benefits in women, even moderate intake of alcohol in women has been associated with a significantly increased risk for breast cancer. Heavy alcohol intake is associated with an increased incidence of coronary heart disease events, as well as with cardiomyopathy, arrhythmia, and other adverse health effects and obviously should be discouraged.
Lack of physical activity is a major modifiable risk factor for CHD. A sedentary lifestyle augments the lipid and nonlipid risk factors of the metabolic syndrome. Inactivity may enhance risk by impairing cardiovascular fitness and coronary blood flow. Regular physical activity reduces very low-density lipoprotein (VLDL) levels, raises HDL-C levels, and, in some persons, lowers LDL levels. It can also lower blood pressure, reduce insulin resistance, and favorably influence cardiovascular function.
Most health benefits occur with at least 150 minutes a week of moderate-intensity physical activity, such as brisk walking. Additional benefits occur with more physical activity.
The ATP III therefore recommends that regular physical activity become a routine component in the management of high serum cholesterol levels. The evidence base for this recommendation is contained in the US Surgeon General's Report on Physical Activity.
Additional Therapies for Atherosclerosis
Partial ileal bypass is a surgical procedure that uses shortening of the ileum to lower circulating cholesterol levels. It has been used since the 1960s for the treatment of hyperlipidemia. Chelation therapy, using intravenous ethylenediaminetetraacetic acid and/or hydrogen peroxide, is a controversial treatment for atherosclerosis. Plethysmography/extracorporeal counterpulsation may reduce angina and improve exercise tolerance in patients with CAD, possibly by improving vascular endothelial function.
Stable Coronary Artery Disease after Intervention
Patients presenting with stable angina or ischemia after physiologic testing and who have undergone revascularization therapy, either in the form of PCI or CABG, benefit from adjuvant pharmacologic therapy and aggressive risk reduction. In post-PCI patients, adjuvant pharmacologic therapy, such as administration of intravenous glycoprotein IIb/IIIa inhibitors (eg, eptifibatide, abciximab), oral aspirin, clopidogrel, or ticlopidine, significantly reduces adverse cardiovascular outcomes. Consultation with a cardiac rehabilitation team is recommended for assistance with aggressive risk reduction, which comprises smoking cessation, weight management, physical exercise, and lipid control.
Consultation with the following may be indicated:
Nutritionists and dietitians
Cardiac rehabilitation team
Consultation with a cardiac rehabilitation team for assistance with smoking cessation, weight management, physical exercise, and lipid control is recommended.
Anderson JL, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interve... J Am Coll Cardiol. 2007 Aug 14. 50(7):e1-e157. [Medline].
Nainggolan L. Surgery is best for most patients, final SYNTAX data confirm. Heartwire. Medscape. Nov 1, 2012. Available at http://www.medscape.com/viewarticle/773741. Accessed: November 19, 2012.
SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries. ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct2/show/NCT00114972. Accessed: November 19, 2012.
Abramowitz Y, Roth A, Keren G, et al. Whole-exome sequencing in individuals with multiple cardiovascular risk factors and normal coronary arteries. Coron Artery Dis. 2016 Jun. 27 (4):257-66. [Medline].
Samady H, Eshtehardi P, McDaniel MC, et al. Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease. Circulation. 2011 Aug 16. 124(7):779-88. [Medline].
Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med. 2003 Dec 11. 349(24):2316-25. [Medline].
Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1995 Sep 1. 92(5):1355-74. [Medline].
Ross R, Fuster V. The pathogenesis of atherosclerosis. Ross R, Fuster V, Topol EJ eds. Atherosclerosis and Coronary Artery Disease. Philadelphia, PA: Lippincott-Raven; 1996. 441-62.
Pencina MJ, D''Agostino RB Sr, Larson MG, Massaro JM, Vasan RS. Predicting the 30-year risk of cardiovascular disease: the framingham heart study. Circulation. 2009 Jun 23. 119(24):3078-84. [Medline]. [Full Text].
[Guideline] Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010 Dec 14. 56(25):e50-103. [Medline]. [Full Text].
[Guideline] Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, et al. Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women--2011 Update: A Guideline From the American Heart Association. Circulation. 2011 Feb 16. [Medline].
Nakano T, Ninomiya T, Sumiyoshi S, Fujii H, Doi Y, Hirakata H, et al. Association of kidney function with coronary atherosclerosis and calcification in autopsy samples from Japanese elders: the Hisayama study. Am J Kidney Dis. 2010 Jan. 55(1):21-30. [Medline].
Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jansen-McWilliams L. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997 Mar 1. 145(5):408-15. [Medline].
Chung CP, Oeser A, Raggi P, Gebretsadik T, Shintani AK, Sokka T, et al. Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors. Arthritis Rheum. 2005 Oct. 52(10):3045-53. [Medline].
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002 Dec 4. 288(21):2709-16. [Medline].
Deo R, Vittinghoff E, Lin F, et al. Risk factor and prediction modeling for sudden cardiac death in women with coronary artery disease. Arch Intern Med. 2011 Oct 24. 171(19):1703-9. [Medline].
Semba RD, Cappola AR, Sun K, et al. Plasma Klotho and Cardiovascular Disease in Adults. J Am Geriatr Soc. 2011 Aug 24. [Medline].
Guallar-Castillon P, Rodriguez-Artalejo F, et al. Consumption of fried foods and risk of coronary heart disease: Spanish cohort of the European Prospective Investigation into Cancer and Nutrition study. BMJ. 2012 Jan 23. 344:e363. [Medline]. [Full Text].
Schrott HG, Bittner V, Vittinghoff E, Herrington DM, Hulley S. Adherence to National Cholesterol Education Program Treatment goals in postmenopausal women with heart disease. The Heart and Estrogen/Progestin Replacement Study (HERS). The HERS Research Group. JAMA. 1997 Apr 23-30. 277(16):1281-6. [Medline].
Vittinghoff E, Shlipak MG, Varosy PD, Furberg CD, Ireland CC, Khan SS, et al. Risk factors and secondary prevention in women with heart disease: the Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2003 Jan 21. 138(2):81-9. [Medline].
Pullen LC. Coronary CT Angiography Predicts Cardiovascular Risk. Medscape Medical News. Dec 6 2013. [Full Text].
Conti A, Poggioni C, Viviani G, Luzzi M, Vicidomini S, Zanobetti M, et al. Short- and long-term cardiac events in patients with chest pain with or without known existing coronary disease presenting normal electrocardiogram. Am J Emerg Med. 2012 Mar 16. [Medline].
Paynter NP, Mazer NA, Pradhan AD, et al. Cardiovascular Risk Prediction in Diabetic Men and Women Using Hemoglobin A1c vs Diabetes as a High-Risk Equivalent. Arch Intern Med. 2011 Oct 24. 171(19):1712-8. [Medline]. [Full Text].
[Guideline] Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB Sr, Gibbons R, et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. [Medline]. [Full Text].
Chou R, for the High Value Care Task Force of the American College of Physicians. Cardiac screening with electrocardiography, stress echocardiography, or myocardial perfusion imaging: advice for high-value care from the American College of Physicians. Ann Intern Med. 2015 Mar 17. 162(6):438-47. [Medline].
O'Riordan M. Less Is More? Multistage CVD Screening Could Eliminate LDL Lab Tests. Medscape Medical News. Available at http://www.medscape.com/viewarticle/819472. Accessed: January 26, 2014.
Pandya A, Weinstein MC, Salomon JA, Cutler D, Gaziano TA. Who needs laboratories and who needs statins?: comparative and cost-effectiveness analyses of non-laboratory-based, laboratory-based, and staged primary cardiovascular disease screening guidelines. Circ Cardiovasc Qual Outcomes. 2014 Jan 1. 7(1):25-32. [Medline].
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004 Aug 4. 44(3):720-32. [Medline].
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 Dec 17. 106(25):3143-421. [Medline].
Stone NJ, Bilek S, Rosenbaum S. Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options. Am J Cardiol. 2005 Aug 22. 96(4A):53E-59E. [Medline].
Ridker PM, Manson JE, Buring JE, Goldhaber SZ, Hennekens CH. The effect of chronic platelet inhibition with low-dose aspirin on atherosclerotic progression and acute thrombosis: clinical evidence from the Physicians' Health Study. Am Heart J. 1991 Dec. 122(6):1588-92. [Medline].
Wallentin L, Husted S, Kontny F, Swahn E. Long-term low-molecular-weight heparin (Fragmin) and/or early revascularization during instability in coronary artery disease (the FRISC II Study). Am J Cardiol. 1997 Sep 4. 80(5A):61E-63E. [Medline].
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996 Oct 3. 335(14):1001-9. [Medline].
Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006 Dec 21. 355(25):2631-9. [Medline].
Ladwiniec A, Ettelaie C, Cunnington MS, et al. Biomarkers of coronary endothelial health: correlation with invasive measures of collateral function, flow and resistance in chronically occluded coronary arteries and the effect of recanalization. Coron Artery Dis. 2016 Jun. 27 (4):287-94. [Medline].
Einstein AJ, Johnson LL, Bokhari S, Son J, Thompson RC, Bateman TM, et al. Agreement of visual estimation of coronary artery calcium from low-dose CT attenuation correction scans in hybrid PET/CT and SPECT/CT with standard Agatston score. J Am Coll Cardiol. 2010 Nov 30. 56(23):1914-21. [Medline].
Ferket BS, Genders TS, Colkesen EB, et al. Systematic review of guidelines on imaging of asymptomatic coronary artery disease. J Am Coll Cardiol. 2011 Apr 12. 57(15):1591-600. [Medline].
Bamberg F, Sommer WH, Hoffmann V, et al. Meta-analysis and systematic review of the long-term predictive value of assessment of coronary atherosclerosis by contrast-enhanced coronary computed tomography angiography. J Am Coll Cardiol. 2011 Jun 14. 57(24):2426-36. [Medline].
Glineur D, D'hoore W, de Kerchove L, et al. Angiographic predictors of 3-year patency of bypass grafts implanted on the right coronary artery system: A prospective randomized comparison of gastroepiploic artery, saphenous vein, and right internal thoracic artery grafts. J Thorac Cardiovasc Surg. 2011 Nov. 142(5):980-8. [Medline].
Wood S. Predicting coronary plaque rupture: new review IDs high-risk signs. Medscape Medical News. May 7, 2014. [Full Text].
Maurovich-Horvat P, Ferencik M, Voros S, Merkely B, Hoffmann U. Comprehensive plaque assessment by coronary CT angiography. Nat Rev Cardiol. 2014 Apr 22. [Medline].
Min JK, Dunning A, Lin FY, et al. Age- and Sex-Related Differences in All-Cause Mortality Risk Based on Coronary Computed Tomography Angiography Findings Results From the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 Patients Without Known Coronary Artery Disease. J Am Coll Cardiol. 2011 Aug 16. 58(8):849-60. [Medline].
O'Rourke RA, Brundage BH, Froelicher VF, Greenland P, Grundy SM, Hachamovitch R, et al. American College of Cardiology/American Heart Association Expert Consensus Document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease. J Am Coll Cardiol. 2000 Jul. 36(1):326-40. [Medline].
Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993 Jun. 87(6):1781-91. [Medline].
Greenwood JP, Motwani M, Maredia N, Brown JM, Everett CC, Nixon J, et al. Comparison of Cardiovascular Magnetic Resonance and Single-Photon Emission Computed Tomography in Women with Suspected Coronary Artery Disease from the CE-MARC Trial. Circulation. 2013 Dec 19. [Medline].
Mc Ardle BA, Dowsley TF, Dekemp RA, Wells GA, Beanlands RS. Does Rubidium-82 PET Have Superior Accuracy to SPECT Perfusion Imaging for the Diagnosis of Obstructive Coronary Disease?: A Systematic Review and Meta-Analysis. J Am Coll Cardiol. 2012 Sep 22. [Medline].
Boggs W. PET Superior to SPECT for Imaging Occlusive Coronary Disease. Medscape Medical News. Available at http://www.medscape.com/viewarticle/772063. Accessed: October 15, 2012.
Murthy VL, Naya M, Foster CR, et al. Improved cardiac risk assessment with noninvasive measures of coronary flow reserve. Circulation. 2011 Nov 15. 124(20):2215-24. [Medline].
Koo BK, Erglis A, Doh JH, et al. Diagnosis of Ischemia-Causing Coronary Stenoses by Noninvasive Fractional Flow Reserve Computed From Coronary Computed Tomographic Angiograms Results From the Prospective Multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) Study. J Am Coll Cardiol. 2011 Nov 1. 58(19):1989-97. [Medline].
El-Shafei A, Chiravuri R, Stikovac MM, El-Badry MA, Donohue TJ, Bach RG. Comparison of relative coronary Doppler flow velocity reserve to stress myocardial perfusion imaging in patients with coronary artery disease. Catheter Cardiovasc Interv. 2001 Jun. 53(2):193-201. [Medline].
Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes : an intravascular ultrasound study. Circulation. 2000 Feb 15. 101(6):598-603. [Medline].
Brooks M. Combo Therapy an Option When Statin Monotherapy Isn't: Study. Medscape. Feb 10 2014. [Full Text].
Gudzune KA, Monroe AK, Sharma R, et al. Effectiveness of combination therapy with statin and another lipid-modifying agent compared with intensified statin monotherapy: a systematic review. Ann Intern Med. 2014 Feb 11. [Medline]. [Full Text].
Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15. 365(24):2255-67. [Medline].
Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011 Nov 16. 306(19):2099-109. [Medline].
Winchester, DE, et al. Evidence of pre-procedural statin therapy a meta-analysis of randomized trials. J Am Coll Cardiol. 2010. 56(14):1099-109.
Kulik A, Voisine P, Mathieu P, et al. Statin Therapy and Saphenous Vein Graft Disease After Coronary Bypass Surgery: Analysis From the CASCADE Randomized Trial. Ann Thorac Surg. 2011 Oct. 92(4):1284-91. [Medline].
Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010 Dec 4. 376(9756):1916-22. [Medline].
O'Riordan M. New Cholesterol Guidelines Abandon LDL Targets. Medscape Medical News. Available at http://www.medscape.com/viewarticle/814152. Accessed: November 18, 2013.
[Guideline] Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013 Nov 12. [Medline].
Pencina MJ, Navar-Boggan AM, D'Agostino RB, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. March/2014. [Full Text].
O'Riordan M. New guidelines extend statins to 13M more Americans. Heartwire. March 19, 2014. [Full Text].
Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med. 2002 Dec 9-23. 162(22):2597-604. [Medline].
Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, et al. Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care. 2003 May. 26(5):1513-7. [Medline].
Pitt B, O'Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001 May 1. 87(9):1058-63. [Medline].
Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S, et al. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation. 2001 Feb 20. 103(7):919-25. [Medline].
Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996 Aug 1. 94(3):258-65. [Medline].
Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol. 2012 Feb 7. 59(6):572-82. [Medline].
Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999 Feb 20. 353(9153):611-6. [Medline].
Hegele RA. Angiotensin-converting enzyme (ACE) inhibition in the secondary prevention of vascular disease: the Heart Outcomes Prevention Evaluation (HOPE) Trial and its substudies. Curr Atheroscler Rep. 2000 Sep. 2(5):361-2. [Medline].
Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Antiplatelet Trialists' Collaboration. Br Med J (Clin Res Ed). 1988 Jan 30. 296(6618):320-31. [Medline]. [Full Text].
Caprie Group. [New analysis of CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) shows: myocardial infarct most effectively prevented in the clopidogrel group]. Z Kardiol. 1998 Feb. 87(2 Suppl Herzinfark):1-4. [Medline].
Mehta SR, Yusuf S. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J. 2000 Dec. 21(24):2033-41. [Medline].
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15. 357(20):2001-15. [Medline].
Boggs W. Low-dose prasugrel effective in elderly heart patients. Medscape Medical News. June 10, 2013. [Full Text].
Erlinge D, Gurbel PA, James S, Lindahl TL, Svensson P, Ten Berg JM, et al. Prasugrel 5-mg in the very elderly attenuates platelet inhibition but maintains non-inferiority to prasugrel 10-mg in non-elderly patients: The GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. J Am Coll Cardiol. 2013 Jun 6. [Medline].
Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010 Dec 14. 122(24):2619-33. [Medline].
Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002 Jul 3. 288(1):49-57. [Medline].
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17. 288(3):321-33. [Medline].
Rossouw JE. Hormones for coronary disease-full circle. Lancet. 2002 Dec 21-28. 360(9350):1996-7. [Medline].
Anderson JL, Muhlestein JB, Carlquist J, Allen A, Trehan S, Nielson C, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: The Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation. 1999 Mar 30. 99(12):1540-7. [Medline].
Cercek B, Shah PK, Noc M, Zahger D, Zeymer U, Matetzky S, et al. Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet. 2003 Mar 8. 361(9360):809-13. [Medline].
Stone AF, Mendall MA, Kaski JC, Edger TM, Risley P, Poloniecki J, et al. Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation. 2002 Sep 3. 106(10):1219-23. [Medline].
Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005 Apr 21. 352(16):1637-45. [Medline].
Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med. 2005 Apr 21. 352(16):1646-54. [Medline].
Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks MM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet. 2009 Apr 4. 373(9670):1190-7. [Medline].
Onuk T, Gungor B, Ipek G, et al. Comparison of long-term prognostic value of baseline SYNTAX and clinical SYNTAX scores in ST-segment elevation myocardial infarction patients with multivessel disease. Coron Artery Dis. 2016 Jun. 27 (4):311-8. [Medline].
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 Apr 12. 356(15):1503-16. [Medline].
Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011 Jan 20. 364(3):226-35. [Medline].
Stiles S. ESC refreshes guidelines for stable CAD, CVD with diabetes. Heartwire. September 2, 2013. [Full Text].
Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al. 2013 ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013 Aug 30. [Medline].
Ryden L, Grant PJ, Anker SD, et al, for the European Society of Cardiology, European Association for the Study of Diabetes Task Forces. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013 Aug 30. [Medline].
Sinha R, Cross AJ, Graubard BI, Leitzmann MF, Schatzkin A. Meat intake and mortality: a prospective study of over half a million people. Arch Intern Med. 2009 Mar 23. 169(6):562-71. [Medline]. [Full Text].
Ferdowsian HR, Barnard ND. Effects of plant-based diets on plasma lipids. Am J Cardiol. 2009 Oct 1. 104(7):947-56. [Medline].
Streppel MT, Ocke MC, Boshuizen HC, Kok FJ, Kromhout D. Long-term wine consumption is related to cardiovascular mortality and life expectancy independently of moderate alcohol intake: the Zutphen Study. J Epidemiol Community Health. 2009 Jul. 63(7):534-40. [Medline].
Djousse L, Lee IM, Buring JE, Gaziano JM. Alcohol consumption and risk of cardiovascular disease and death in women: potential mediating mechanisms. Circulation. 2009 Jul 21. 120(3):237-44. [Medline]. [Full Text].
Lew JQ, Freedman ND, Leitzmann MF, Brinton LA, Hoover RN, Hollenbeck AR. Alcohol and risk of breast cancer by histologic type and hormone receptor status in postmenopausal women: the NIH-AARP Diet and Health Study. Am J Epidemiol. 2009 Aug 1. 170(3):308-17. [Medline]. [Full Text].
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18. 372 (25):2387-97. [Medline]. [Full Text].
ODYSSEY outcomes: Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab SAR236553 (REGN727). NCT01663402. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT01663402. July 10, 2015; Accessed: July 27, 2015.
Sabatine MS, Giugliano RP, Wiviott SD, et al, for the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16. 372 (16):1500-9. [Medline].
Koren MJ, Giugliano RP, Raal FJ, et al, for the OSLER Investigators. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014 Jan 14. 129 (2):234-43. [Medline]. [Full Text].
Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010 Dec 16. 363(25):2406-15. [Medline].
Denton TA, Fonarow GC, LaBresh KA, Trento A. Secondary prevention after coronary bypass: the American Heart Association "Get with the Guidelines" program. Ann Thorac Surg. 2003 Mar. 75(3):758-60. [Medline].
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16. 333(20):1301-7. [Medline].
Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999 Dec 13-27. 159(22):2661-7. [Medline].
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19. 344(8934):1383-9. [Medline].
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998 May 27. 279(20):1615-22. [Medline].
Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011 Dec 1. 365(22):2078-87. [Medline].
US Food and Drug Administration. FDA approves Praluent to treat certain patients with high cholesterol [press release]. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. July 24, 2015.; Accessed: July 31, 2015.
AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15. 365 (24):2255-67. [Medline]. [Full Text].
HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014 Jul 17. 371 (3):203-12. [Medline]. [Full Text].
Wending P. FDA pulls approval of niacin, fibrate in combo with statins. Heartwire from Medscape Medical News. Available at http://www.medscape.com/viewarticle/862022. April 15, 2016; Accessed: April 15, 2016.
Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet. 1995 May 20. 345(8960):1274-5. [Medline].
Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006 Apr 20. 354(16):1706-17. [Medline].
Bild DE, Bluemke DA, Burke GL, Detrano R, Diez Roux AV, Folsom AR, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol. 2002 Nov 1. 156(9):871-81. [Medline].
Blumenthal RS, Michos ED. The HALTS trial--halting atherosclerosis or halted too early?. N Engl J Med. 2009 Nov 26. 361(22):2178-80. [Medline].
Brown BG, Hillger L, Zhao XQ, Poulin D, Albers JJ. Types of change in coronary stenosis severity and their relative importance in overall progression and regression of coronary disease. Observations from the FATS Trial. Familial Atherosclerosis Treatment Study. Ann N Y Acad Sci. 1995 Jan 17. 748:407-17; discussion 417-8. [Medline].
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004 Aug 21-27. 364(9435):685-96. [Medline].
Farmer JA, Gotto AM. Dyslipidemia and other risk factors for coronary artery disease. Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia, PA: WB Saunders; 1997. 1126-60.
Gotto AM Jr, Farmer JA. Reducing the risk for stroke in patients with myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy. Circulation. 2002 Sep 24. 106(13):1595-8. [Medline].
Howard BV, Rodriguez BL, Bennett PH, Harris MI, Hamman R, Kuller LH. Prevention Conference VI: Diabetes and Cardiovascular disease: Writing Group I: epidemiology. Circulation. 2002 May 7. 105(18):e132-7. [Medline].
Kastelein JJ, Bots ML. Statin therapy with ezetimibe or niacin in high-risk patients. N Engl J Med. 2009 Nov 26. 361(22):2180-3. [Medline].
Keating GM, Robinson DM. Rosuvastatin: a review of its effect on atherosclerosis. Am J Cardiovasc Drugs. 2008. 8(2):127-46. [Medline].
Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009 Jan 27. 119(3):e21-181. [Medline].
Maher VM, Brown BG, Marcovina SM, Hillger LA, Zhao XQ, Albers JJ. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA. 1995 Dec 13. 274(22):1771-4. [Medline].
Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002 Dec 18. 288(23):2998-3007. [Medline].
Michael H. Merson, Robert E. Black, Anne Mills. Chronic Diseases and Risks. International public health: diseases, programs, systems, and policies. Sudbury, MA: Jones and Bartlett Publishers; 2006.
Mills NL, Donaldson K, Hadoke PW, Boon NA, MacNee W, Cassee FR, et al. Adverse cardiovascular effects of air pollution. Nat Clin Pract Cardiovasc Med. 2009 Jan. 6(1):36-44. [Medline].
O'Keefe JH, Carter MD, Lavie CJ, Bell DS. The gravity of JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin). Postgrad Med. 2009 May. 121(3):113-8. [Medline].
Physical Activity Guidelines Advisory Committee. 2008 Physical Activity Guidelines for Americans. US Department of Health and Human Services. Available at. Available at http://www.health.gov/paguidelines/Report/Default.aspx. Accessed: 5/28/2010.
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998 Nov 5. 339(19):1349-57. [Medline].
Ridker PM. Evaluating novel cardiovascular risk factors: can we better predict heart attacks?. Ann Intern Med. 1999 Jun 1. 130(11):933-7. [Medline].
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009 Apr 4. 373(9670):1175-82. [Medline].
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20. 359(21):2195-207. [Medline].
Ronner E, Boersma E, Laarman GJ, Somsen GA, Harrington RA, Deckers JW, et al. Early angioplasty in acute coronary syndromes without persistent ST-segment elevation improves outcome but increases the need for six-month repeat revascularization: an analysis of the PURSUIT Trial. Platelet glycoprotein IIB/IIIA in Unstable angina: Receptor Suppression Using Integrilin Therapy. J Am Coll Cardiol. 2002 Jun 19. 39(12):1924-9. [Medline].
Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14. 340(2):115-26. [Medline].
Scanu AM, Bamba R. Niacin and lipoprotein(a): facts, uncertainties, and clinical considerations. Am J Cardiol. 2008 Apr 17. 101(8A):44B-47B. [Medline].
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002 Nov 23. 360(9346):1623-30. [Medline].
Singh V, Deedwania P. Expanding roles for atorvastatin. Drugs Today (Barc). 2008 Jun. 44(6):455-71. [Medline].
Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26. 361(22):2113-22. [Medline].
West of Scotland Coronary Prevention Study: implications for clinical practice. The WOSCOPS Study Group. Eur Heart J. 1996 Feb. 17(2):163-4. [Medline].
Yerokun BA, Williams JB, Gaca J, Smith PK, Roe MT. Indications, algorithms, and outcomes for coronary artery bypass surgery in patients with acute coronary syndromes. Coron Artery Dis. 2016 Jun. 27 (4):319-26. [Medline].