Coronary Artery Atherosclerosis Treatment & Management
- Author: F Brian Boudi, MD; Chief Editor: Yasmine Subhi Ali, MD, MSCI, FACC, FACP more...
Approach Considerations
The treatment goals for patients with coronary artery atherosclerosis are to relieve symptoms of 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.[37] 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.
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.
Pharmacologic Strategies
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. 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.[38]
In a meta-analysis of nearly 5000 patients, findings showed that statins administered before invasive procedures significantly reduced the risk for postprocedural myocardial infarction.[39] 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.
The Clopidogrel After Surgery for Coronary Artery Disease CASCADE trial evaluated the addition of clopidogrel to aspirin on the development of saphenous vein graft disease after CABG. Patients received the standard of care, including postoperative statin therapy with targeted LDL levels less than 100 mg/dL. Twelve months postoperatively, patients returned for coronary angiography and saphenous vein graft (SVG) intravascular ultrasonography. The results suggest statin therapy to achieve LDL levels less than 100 mg/dL is independently associated with improved graft patency.[40]
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.[41]
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.
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.[42]
To see complete information on Statins, please go to the main article.
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.[43, 44]
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.[45]
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.[46]
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),[47] 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.[48]
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.[49]
A possible direct effect of ACE inhibitors on atherosclerosis, independent of blood pressure reduction, was suggested by the Heart Outcomes Prevention Evaluation (HOPE) study,[50] 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[51]
- Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial[52]
- Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial[53]
- Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes (TRITON TIMI-38)[54]
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.[52] 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.
ACC/AHA guidelines recommend that after an ACS, all patients should receive dual antiplatelet therapy, ideally for 12 months, followed by lifelong aspirin therapy.[37] The ACCF/ACG/AHA 2010 Expert Consensus provides a detailed report on reducing the GI risks of antiplatelet therapy and NSAID Uuse.[55]
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).[37]
Beta-blockers
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
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
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.[15] 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.[56]
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.[57]
Because of overall increased risk, combined estrogen and progestin therapy should not be initiated or continued for primary prevention of CAD.[58]
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,[59] the Azithromycin in Acute Coronary Syndrome (AZACS) study,[60] the South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA),[61] the Azithromycin Coronary Events Study (ACES),[62] and the antibiotic arm of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial[63] all returned negative results in terms of any significant benefit from antibiotic therapy.
Revascularization Procedures
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 is similar after CABG and PCI in most patient subgroups with multivessel coronary artery disease; therefore, the choice of treatment should depend 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.[64] 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).[65]
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.[66] Major adverse events were related to both recurrence at the site of culprit lesions and to nonculprit lesions.
Lifestyle Changes
Diet
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.[67]
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.[68]
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)
- Weight reduction
- 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.[69] The mechanism(s) of this benefit is not well understood. Although alcohol may have cardiovascular benefits in women,[70] even moderate intake of alcohol in women has been associated with a significantly increased risk for breast cancer.[71] 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.
Physical activity
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.[60]
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.
Consultations
Consultation with the following may be indicated:
- Cardiologists
- Cardiovascular surgeons
- Lipidologists
- Nutritionists and dietitians
- Cardiac rehabilitation team
- Radiologists
Consultation with a cardiac rehabilitation team for assistance with smoking cessation, weight management, physical exercise, and lipid control is recommended.
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