eMedicine Specialties > Cardiology > Atherosclerosis and Risk Factors

Coronary Artery Atherosclerosis: Treatment & Medication

Author: Vibhuti N Singh, MD, MPH, FACC, FSCAI, Director, Suncoast Cardiovascular Center; Chair, Cardiology Division and Cath Labs, Department of Medicine, Bayfront Medical Center; Clinical Assistant Professor, Division of Cardiology, University of South Florida College of Medicine
Coauthor(s): Prakash C Deedwania, MD, FACC, FAHA, FACP, FCCP, Professor of Medicine, University of California, San Francisco School of Medicine; Chief, Cardiology Section, Veterans Affairs Medical Center, UCSF Program at Fresno, California; Director, Cardiovascular Research, UCSF Central San Joaquin Program; Rakesh K Sharma, MD, FACC, Adjunct Associate Professor of Medicine and Cardiology; University of Arkansas for Medical Sciences, Medical Center of South Arkansas
Contributor Information and Disclosures

Updated: Oct 29, 2009

Treatment

Medical Care

The treatment goals for patients with coronary artery atherosclerosis are to relieve symptoms and to prevent future cardiac events such as unstable angina, AMI, and death.

Relief of symptoms

• Typically, patients with CAD are first seen after they present with a cardiac event. The main focus of their treatment is treating 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 percutaneous intervention.
• The use of adjunctive therapy in the form of glycoprotein IIb/IIIa inhibitors has failed to show additional mortality benefit in large trials such as the Global Use of Strategies To Open Occluded Coronary Arteries in Acute Myocardial Infarction-V (GUSTO-V) trial¹⁷ and the Assessment of the Safety and Efficacy of New Thrombolytic Regimens-3 (ASSENT-3) trial¹⁸ .

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. However, 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 CAD or even reversing its progression. High-risk subgroups, in particular, can be targeted for early intervention. Grover and colleagues have shown 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 LDL reduction or the administration of agents that alter the atherosclerotic plaque, are of paramount importance in this regard.
  • The current understanding of CAD suggests that luminal stenosis is not the only cause of acute coronary events; instead, a perpetual inflammatory process leads to plaque formation and its growth with glagovian remodeling with a thin, fibrous cap that ruptures, thus extruding the thrombogenic lipid pool and causing thrombotic luminal occlusion and MI.
  • Large, multicenter randomized trials of various pharmacologic modalities have recently achieved great success in the treatment of patients with coronary artery atherosclerosis.

Statins

The introduction of statins has prompted significant advances in the management of CAD. Over the past decade, several large-scale trials of cholesterol-reducing agents, particularly statins, have unequivocally proven the lipid hypothesis and provided substantial evidence of the advantages of lipid management in various subgroups of patients.¹⁹

• Mechanism of therapeutic effect
  • Statins decrease the number of cardiovascular events by retarding the progression of atherosclerosis, stopping new lesion development, stabilizing the existing plaques, and reducing subintimal inflammation.
  • Previous studies examined the effect of statins on CAD progression. A review of 9 angiographic regression studies indicates that while angiographic changes caused by insignificant plaque reduction were small, the associated clinical responses appeared significantly greater.
  • In 1997, Thompson²⁰ performed a meta-analysis of these trials and suggested a lower goal for LDL levels than the one currently recommended by the Adult Treatment Panel III (ATP-III) guidelines. Generally, a 45% reduction in the LDL level is needed to almost fully stop the progression of atherosclerosis. Apparently, a greater effect is observed on newer or minimal lesions than on older plaques, as was shown by the Pravastatin Limitation of Atherosclerosis in Coronary Arteries (PLAC)-1 study and the Multicenter Anti-Atheroma Study (MAAS). B-mode ultrasound was used in 4 trials for assessment of the antiatherosclerotic effect of statins. All of the trials showed a consistent benefit on plaque reduction in peripheral arteries.
  • In the past decade, large controlled clinical trials have shown benefit in the primary and secondary prevention of CAD in subjects with elevated serum cholesterol levels. The efficacy of statins has recently been extended to include primary prevention of CAD in patients with average cholesterol levels.
  • Apart from lowering LDL levels, statins have been shown in vitro to influence several other components of the atherosclerotic process. For example, statins cause (1) decreased cholesterol esterification, LDL oxidation, and macrophage uptake of oxLDL (a putative stimulus that initiates endothelial cell adhesion); (2) reduced SMC proliferation and/or migration; (3) decreased monocyte-endothelial cell adhesion; (4) reduction in the expression of adhesion molecules; (5) a lessening of tissue factor expression and an increase in endothelial nitric oxide synthetase III level; (6) reduced vascular A-II levels; and (7) anti-inflammatory effects (decrease in CRP).
• Clinical studies
  • The meta-analysis of 5 major statin trials totaling more than 30,000 subjects provides indisputable evidence of the effectiveness of statins in a variety of patient subgroups over a 5- to 6-year follow-up period.
  • These studies include the West of Scotland Coronary Prevention Study (WOSCOPS) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) for primary prevention and the Scandinavian Simvastatin Survival Study (4S), CARE, and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trials for secondary prevention. On average, statin therapy produced a 20% reduction in total cholesterol levels, a 28% reduction in LDL levels, and a 13% reduction in triglyceride levels, along with a 5% rise in HDL levels.
  • Overall, the number of coronary events and coronary deaths was reduced by 31% and 29%, respectively. The total mortality rate was decreased by 21% (P <.001), and cardiovascular mortality was decreased by 27% (P <.001). Rate reductions of cardiovascular events were similar between males and females and in persons older than 65 years and those younger than 65 years.
  • Most of the post-MI studies with statins did not begin administration of the drug for 3-6 months after the MI. Ironically, statins affect endothelial function and could be of benefit if begun early. An analysis of the GUSTO and Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) studies showed that patients who were on lipid-lowering treatment at the time of hospital discharge had a 33% lower mortality rate at 6 months compared with those who were not.²¹ A Swedish registry exhibited a similar reduction in 1-year mortality rates in patients who were started on antilipid treatment in the hospital.
  • A prospective study, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL), recently evaluated the benefits of starting 80 mg of atorvastatin within 24-96 hours of admission for ACS.²² Such early introduction of statin therapy caused a 16% decrease in the incidence of nonfatal MI, cardiac arrest, or recurrent ischemic symptoms over a 16-week follow-up period. The mortality rate was not reduced, but the trial was not designed to investigate this endpoint. Additionally, 2 studies (Aggrastat to Zocor [A to Z], PROVE IT) are assessing the effects of statin use in persons with ACS.
• Management guidelines
  • The NCEP ATP III guidelines suggest a goal LDL-C level of less than 130 mg/dL for everyone and less than 100 mg/dL for patients with known CAD. Whether more aggressive LDL lowering would provide additional benefit is unclear.
  • A target LDL-C level of 100 mg/dL (rather than 130 mg/dL) was shown to be more beneficial by the Post-Coronary Artery Bypass Graft Trial (PCABGT) involving 1350 subjects. Sequential reduction of LDL levels in a subgroup analysis of the 4S study exhibited further event reduction with each quartile of lipid lowering. A newer trial, the Treating to New Targets (TNT) trial, is underway and is comparing LDL reduction to less than 100 mg/dL with reduction to less than 75 mg/dL with atorvastatin in approximately 10,000 subjects with CAD.
  • Two other end-point trials in progress include the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) and the Incremental Decrease in Endpoints through Aggressive Lipid-Lowering (IDEAL) study.
• Significance of treating low HDL levels and high triglyceride levels
  • This lipid pattern is frequently encountered in diabetic patients. Most of these patients fit into the category of dysmetabolic syndrome.
  • Two of the trials currently in progress include Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Lipids in Diabetes Study (LDS). These studies are assessing the benefits of fibrates—alone or in combination with statins—to raise HDL levels and to reduce triglyceride levels.
• Safety
  • Despite the withdrawal of cerivastatin (Baycol) from the market because of serious adverse effects, all other statins currently available on the market are very safe and effective.
  • Statins are well tolerated. The percentage of patients experiencing adverse effects approaches that of patients on placebo. Liver function should be monitored, and musculoskeletal syndromes should be sought.
• Recent trials of most significant impact
  • The lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) examined the benefits of cholesterol lowering in the primary prevention of CAD in hypertensive patients who are not conventionally deemed dyslipidemic. The study was stopped prematurely because of a significant 36% reduction in the primary endpoints (ie, nonfatal MI, fatal CHD). In hypertensive patients who achieved good blood pressure control, LDL-C lowering produced clinically significant additional reductions in risk for both CAD and stroke.
  • This is in contrast to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the only other large study performed mainly in hypertensive patients, in which a modest differential in triglycerides and LDL-C levels was obtained between the 2 treatment groups, but a significant benefit was not observed.
  • Most observational studies fail to show cholesterol as a major risk factor for stroke. However, stroke incidence is reduced with LDL-C lowering in most statin trials, mostly in subgroup or retrospective analysis. In the ASCOT-LLA, a 27% stroke reduction was observed in subjects with good blood pressure control and average LDL-C levels.
  • Stroke reduction was also demonstrated for individuals older than 70 years. Previously, the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) trial showed a reduction in CAD events—but not stroke—in elderly patients older than 70 years. The reduction in both CAD and stroke occurred within the first year, suggesting that statin therapy, in addition to antihypertensive therapy, should be initiated early in hypertensive patients. The benefits were consistent across all baseline lipid levels in patients with average LDL-C levels. This study is consistent with the recent PROSPER trial and Heart Protection Study (HPS), which suggest that statin therapy should be initiated based on overall risk status, not simply on baseline lipid levels.
  • Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) was recently published.²³ The trial addressed the issue that even though type 2 diabetes is associated with an enhanced risk of cardiovascular disease, the role of lipid-lowering therapy with statins for primary prevention in this setting is unclear. CARDS examined the effectiveness of atorvastatin at 10 mg/d in such patients who did not have high levels of baseline LDL-C. The 2838 subjects were aged 40-75 years and were being treated in 132 centers in the United Kingdom and Ireland. They were randomized to placebo (n = 1410) or atorvastatin at 10 mg/d (n = 1428). Study entrants had no documented previous history of cardiovascular disease, but they had at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The trial was terminated 2 years earlier than expected, with median follow up of 3.9 years, because the prespecified early stopping rule for efficacy had been met. While 127 patients allocated to placebo (2.46 per 100 person-years at risk) had at least one major cardiovascular event, only 83 subjects allocated to atorvastatin had such events (1.54 per 100 person-years at risk; rate reduction of 37% with 95% confidence interval [CI] of -52 to -17; P = .001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years.Overall, acute coronary events were reduced by 36% (-55 to -9), coronary revascularizations were reduced by 31% (-59 to 16), and strokes were reduced by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, P = .59), which was not significant. No excess adverse events were noted in the atorvastatin group. Thus, atorvastatin at 10 mg/d is considered effective and helps decrease the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high baseline LDL-C levels.
  • The lipid-lowering arm of the ALLHAT examined the effects of lipid-lowering therapy on all-cause mortality and coronary heart disease endpoints in patients with moderate hypercholesterolemia, who were older than 55 years, had mild-to-moderate hypertension plus at least 1 additional risk factor, and had fasting LDL-C levels of 120-189 mg/dL (or 100-129 mg/dL if known CHD). Subjects were randomized to receive pravastatin at 40 mg/d (n = 5170) or usual care (n = 5185) and were followed for up to 8 years. At year 4, pravastatin reduced LDL-C levels by 28%, versus 11% with usual care. However, neither all-cause mortality nor CHD event rates differed significantly between groups. While pravastatin failed to significantly reduce all-cause mortality or CHD compared with usual care in this population (older subjects with well-controlled hypertension and moderately elevated LDL-C), the authors speculated that this may be due to smaller differences in total cholesterol and LDL-C levels between the pravastatin and usual care groups compared with previous statin trials. Overall, 9 large long-term statin trials have supported the safety and efficacy of this treatment in the prevention and treatment of CHD.²⁴
  • The HPS cholesterol-lowering with simvastatin in 5963 subjects with diabetes randomized (1) 5963 adults aged 40-80 years from the United Kingdom known to have diabetes and (2) an additional 14,573 with occlusive arterial disease (but no diagnosed diabetes) to receive simvastatin at 40 mg/d or matching placebo. Both among the participants who presented with diabetes and among those who did not, highly significant reductions of approximately 25% occurred in the first event rate for major coronary events, for strokes, and for revascularizations. For the first occurrence of any of these major vascular events among participants with diabetes, a definite 22% (95% CI, 13-30; P <.0001) reduction in the event rate occurred, which was similar to that among the other high-risk individuals studied. Additionally, highly significant reductions of 33% (95% CI, 17-46; P = .0003) occurred among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry. Finally, a reduction of 27% (95% CI, 12-40; P = .0007) occurred among the 2426 diabetic participants whose pretreatment LDL-C concentration was below 116 mg/dL.Thus, this study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes, even if they do not already have manifestations of coronary disease or high cholesterol concentrations. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent 45 people per 1000 from having at least one major vascular event. Statin therapy should, therefore, be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol levels.
  • The PROSPER trial was designed to examine the efficacy and safety of statins in elderly men and women with, or at high risk of developing, cardiovascular disease and stroke. A group of 5804 men (n = 2804) and women (n = 3000) aged 70-82 years with a history of, or risk factors for, vascular disease were randomized to pravastatin (40 mg/d, n = 2891) or placebo (n = 2913). Baseline cholesterol concentrations ranged from 4-9 mmol/L, and the follow-up period was 3.2 years. The primary endpoint was a composite of coronary death, nonfatal MI, and fatal or nonfatal stroke. Pravastatin lowered LDL-C concentrations by 34% and reduced the incidence of the primary endpoint to 408 events, compared with 473 on placebo (hazard ratio 0.85; 95% CI, 0.74-0.97; P = .014). Coronary heart disease death and nonfatal MI risk was also reduced (hazard ratio, 0.81; 95% CI, 0.69-0.94; P = .006). Stroke risk was unaffected (hazard ratio 1.03; 95% CI, 0.81-1.31; P = .8), but the hazard ratio for transient ischemic attack was 0.75 (95% CI, 0.55-1; P = .051). Mortality from coronary disease fell by 24% (P = .043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. The authors concluded that pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. The PROSPER trial, therefore, extends to elderly individuals the treatment strategy currently used in middle-aged people.²⁵
  • The PROVE-IT (Thrombolysis in Myocardial Infarction [TIMI] 22) trial examined whether statins are effective in reducing events in patients with ACS and whether intensive LDL-C lowering to an average of 65 mg/dL achieves a greater reduction in clinical events than standard LDL-C lowering to an average of 95 mg/dL. The results demonstrated that in patients recently hospitalized for an ACS, intensive LDL-C lowering (median LDL-C level of 62 mg/dL) using high-dose statins (atorvastatin, 80 mg/d) compared with moderate lipid-lowering therapy (median LDL-C level of 95 mg/dL) using moderate-dose statins (pravastatin, 40 mg/d) reduced the risk of all-cause mortality or major cardiac events by an additional 16% (P = .005). These benefits emerged within 30 days post-ACS, with continued benefit observed throughout the 2.5 years of follow-up. Additionally, the benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups.
  • The Aggressive Lipid Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial enrolled 2442 subjects (1:1 randomization) with a history of CHD, defined as AMI more than 3 months before screening, PTCA more than 6 months before screening, and coronary artery bypass graft or unstable angina more than 3 months before screening to atorvastatin (n = 1217) therapy versus usual care (n = 1225) and followed them for 52 months. The atorvastatin dose was initiated at 10 mg and titrated up to 80 mg or until an LDL level of less than 80 mg/dL was achieved. Usual care was defined as the lipid treatment program prescribed by the patient's primary physician and could include diet, weight loss, physical activity, behavior modification, and antihyperlipidemic medication (including atorvastatin). The composite endpoint included cardiac death, nonfatal MI, resuscitated cardiac arrest, revascularization, or unstable angina requiring hospitalization. The baseline LDL level was reduced from 147 mg/dL to 95 mg/dL (56% reduction) in the atorvastatin group and to 111 mg/dL (36% reduction) in the usual care group. The primary endpoint (composite of cardiac death, nonfatal MI, resuscitated cardiac arrest, revascularization, or unstable angina) was reduced by 17% in the atorvastatin group compared with the usual care group. Atorvastatin therapy was associated with a 47% decrease in nonfatal MI versus usual care. The mean dose of atorvastatin in the study was 40.5 mg/d. Intensive lipid lowering with atorvastatin was well tolerated (ie, no myopathy or rhabdomyolysis, and <1.3% rate of aspartate aminotransferase or alanine aminotransferase increase above 3 times normal). These results clearly show the important cardiovascular benefits of intensively lowering cholesterol with atorvastatin and the additional benefits in patients at high risk for recurrent coronary events than it provides for patients already receiving usual care.
  • The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, a double-blinded, randomized multicenter trial, used IVUS to measure progression of atherosclerosis in 654 subjects randomized to receive a moderate lipid-lowering regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering regimen consisting of 80 mg of atorvastatin. The baseline LDL-C level of 150.2 mg/dL was reduced to 110 mg/dL in the pravastatin group and to 79 mg/dL in the atorvastatin group (P <.001). CRP was also measured, and it decreased 5.2% with pravastatin and 36.4% with atorvastatin (P <.001). The percentage change in atheroma volume measured by IVUS showed a significantly lower progression rate in the atorvastatin (intensive) group (P = .02). Overall, while progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; P = .001) compared with baseline, progression did not occur in the atorvastatin group (-0.4%; P = .98). The study concluded that for patients with coronary heart disease, intensive lipid-lowering treatment with atorvastatin significantly reduces the progression of coronary atherosclerosis compared with pravastatin. These differences may be related to the greater reduction in atherogenic lipoproteins and CRP in the patients treated with atorvastatin.The Z phase of the A to Z trial studied an early intensive versus a delayed conservative simvastatin strategy in patients with ACS. Phase Z of the A to Z trial randomized patients with ACS to receive 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) or placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232). Among the subjects in the placebo plus simvastatin group, the median LDL-C level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the subjects in the simvastatin only group, the median LDL-C level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin.A total of 343 subjects (16.7%) in the placebo plus simvastatin group experienced the primary endpoint, compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (P = .14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) subjects in the 2 groups (P = .05). While no difference was evident during the first 4 months between the groups for the primary endpoint (P = .89), from 4 months through the end of the study, the primary endpoint was significantly reduced in the simvastatin only group (P = .02). Myopathy (creatine kinase level >10 times the upper limit of normal and associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin at 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P = .02).This trial did not achieve the prespecified endpoint. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.
• Recent data and the ATP-III update
  • ATP-III of the NCEP 2004 updated guidelines: The ATP III issued an update to its evidence-based guidelines for cholesterol management, initially published in 2001. Five major trials since 2001 addressed some new issues that were not previously examined. TLCs remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of an LDL-C level of less than 100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C levels. The major recommendations for modifications to footnote the ATP III treatment algorithm include the following:
    • 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, on the basis of available clinical trial evidence. This therapeutic option even applies to patients at very high risk who have a baseline LDL-C level of less than 100 mg/dL.
    • Furthermore, when a high-risk patient has a high triglyceride level or low HDL-C level, a strategy of combining a fibrate or nicotinic acid with an LDL-lowering drug should be considered.
    • 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 on the basis of recent trial evidence. The latter option can also be extended to moderately high-risk persons with a baseline LDL-C level of 100-129 mg/dL.
    • When LDL-lowering drug therapy is used in high-risk or moderately high-risk persons, the intensity of therapy should be sufficient to achieve at least a 30-40% reduction in LDL-C levels.
    • In addition, persons at high risk or moderately high risk who have lifestyle-related risk factors, such as obesity, physical inactivity, elevated triglyceride level, low HDL-C level, or metabolic syndrome, are candidates for TLC to modify these risk factors, regardless of LDL-C level.
    • Finally, for persons in lower-risk subsets, recent clinical trials do not modify the goals and cut points of lipid treatment.
  • Veterans Affairs HDL Intervention Trial
    • Recent additional follow-up and analysis of the Veterans Affairs HDL Intervention Trial (VA-HIT) indicate that treatment with gemfibrozil versus placebo resulted in a 32% reduction in major cardiovascular events (P <.004) and a 41% reduction in CHD deaths (P = .02) in 769 male subjects with diabetes mellitus and CHD with HDL-C levels of less than 40mg/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), ie, 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.^26,27
    • 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. One unanswered question is whether body mass index or waist circumference, which strongly correlated with fasting insulin in nondiabetic subjects, could also be used to predict those with greater or lesser CHD risk reduction with gemfibrozil therapy.
    • This is 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

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.

• Mechanism of therapeutic effect
  • ACE inhibitors are effective blood pressure–reducing agents. They also affect the heart and vasculature through direct and other mechanisms.
  • ACE inhibitors were not shown to affect the plaque in a randomized angiographic regression trial, the Quinapril Ischemic Event Trial (QUIET) of 463 subjects with CAD.²⁸ B-mode ultrasound studies investigating plaque regression have also provided confusing results at best. Although the second Prevention of Atherosclerosis with Ramipril Trial (PART 2) showed no reduction in intimal-medial thickness (IMT) 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 IMT proportional to the dose of ramipril (2.5-10 mg/d) in 750 subjects over a 4.5-year follow-up period.²⁹
  • 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) study, 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 (P = .002) to acetylcholine. ACE inhibitors also increase nitric oxide levels by increasing its release through a kinin-mediated pathway and through reduction of its breakdown.
  • ACE inhibitors also 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.
• Clinical studies
  • 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 outcome risk.³⁰
  • 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.
  • Two new studies to evaluate similar endpoints are underway. They include the Prevention of Events with ACE Inhibitors (PEACE) study and the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) study.

Antiplatelet agents (eg, aspirin, clopidogrel)

These agents help reduce the number of acute coronary events. Convincing data are now available from the following studies:

• Antiplatelet Trialists' Collaboration
• Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial³¹
• Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial³²
• Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (PCI-CURE) trial³³

Calcium channel blockers

These agents play a significant role in the treatment of angina or ischemia in symptomatic patients with CAD and are included in the American College of Cardiology/American Heart Association guidelines for stable angina management. Other indications for calcium channel blocker (CCB) therapy include hypertension and use along with diuretics in isolated systolic hypertension.

• Mechanism of therapeutic effect
  • CCBs—both dihydropyridines (eg, nifedipine) and nondihydropyridines (eg, verapamil, diltiazem), as well as the newer agents (eg, amlodipine)—have been shown to reduce atherosclerosis in animal models. This effect appears to be independent of the blood pressure–lowering effect and of the calcium channel blocking properties.
  • Amlodipine has antioxidant effects and normalizes the levels of oxLDL in primates given atherogenic meals. It also augments nitric oxide release. CCBs also inhibit monocyte adhesion, retard growth factor release, decrease SMC proliferation and migration, reduce platelet aggregability, and block cholesterol uptake by macrophages.
• Clinical studies
  • Hypertension trials using CCBs have shown similar benefits to beta-blockers and diuretics. The Nordic Diltiazem (NORDIL) study compared diltiazem with beta-blockers and diuretics in 10,881 subjects.³⁴ The reduction in cardiac mortality and morbidity rates was similar. The International Nifedipine Study - Intervention as a Goal in Hypertension Treatment (INSIGHT) study found nifedipine to be similar to hydrochlorothiazide/amiloride over a 4.5-year follow-up period.³⁵
  • A meta-analysis by the Blood Pressure Trialists' Lowering Treatment Collaboration showed a 30-40% reduction in the number of strokes and cardiac events versus placebo. Comparison with diuretics and beta-blockers, however, showed a 13% greater reduction in stroke but a borderline 12% increase in CAD. The International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) study of 425 subjects showed no significantly different change in atherosclerotic plaque compared with placebo.³⁶ However, new lesion formation was reduced. The Montreal Heart Study, which involved 383 subjects, showed no benefit to nicardipine over placebo.
  • The Multi-Center Isradipine Diuretic Atherosclerosis Study (MIDAS) compared isradipine with hydrochlorothiazide in 883 subjects with hypertension.³⁷ Carotid IMT was lesser in the isradipine group at 6 months; however, subjects receiving isradipine showed a tendency for increased vascular events (P = .07). The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) study randomized 825 subjects to placebo or to amlodipine at 5 mg/d.³⁸ At 3 years, no significant difference was noted between the 2 groups by QCA. B-mode ultrasound measuring carotid IMT, however, showed no progression in the amlodipine group. The combined endpoint of unstable angina and CHF was decreased by 35% (P <.01), and the need for PTCA was reduced by 46%.
  • In the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES) involving 585 post-PTCA subjects randomized to placebo or amlodipine, no significant difference was observed in the rates of angiographic restenosis and clinical events. However, the rate of repeat PTCA was decreased significantly (P = .01).³⁹
  • A large trial, the International Verapamil Trandolapril Study (INVEST), is comparing a CCB strategy with non-CCB strategies in patients with hypertension and prior CAD.⁴⁰
  • In progress are 3 other large trials that seek to assess the effects of amlodipine versus ACE inhibitors. These include the ALLHAT of 40,000 subjects, the ASCOT of 18,000 subjects, and the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) of 3000 subjects. A subgroup of CAMELOT subjects will undergo IVUS assessment as part of the Norvasc for Regression of Manifest Atherosclerotic Lesion Intravascular Sonographic Evaluation (NORMALISE) study.

Hormone replacement therapy

• Hormone replacement therapy has been found to be more risky than beneficial in postmenopausal women in the HERS of secondary prevention and the Women's Health Initiative of primary prevention.⁸ The HERS Follow-up (HERS-II), completed in 2002, reported that after 6.8 years, hormone therapy did not reduce risk of cardiovascular events.⁴¹
• The risks and benefits of estrogen therapy plus progestin in healthy postmenopausal women (ie, primary prevention) were reported as the principal results from the Women's Health Initiative randomized controlled trial (n = 8506 on hormone replacement therapy; n = 8102 on placebo).⁴² Overall health risks exceeded benefits from use of combined estrogen and progestin for an average 5.2-year follow-up period among healthy postmenopausal US women. All-cause mortality was unaffected.
• Because of overall increased risk, this regimen should not be initiated or continued for primary prevention of CAD.⁴³

Medical versus surgical treatment

Teo et al found that among older patients with stable coronary artery disease, optimal medical treatment without percutaneous coronary intervention remains an appropriate initial management strategy. Analysis of 904 patients aged 65 years or older showed that, during a median 4.6-year follow-up, clinical outcome in patients randomized to optimal medical treatment plus PCI was no better or worse than in patients who received optimal medical treatment alone. Compared with 1381 patients younger than 65 years with coronary artery disease, older patients had similar success in achieving treatment targets and similar rates of myocardial infarction, stroke, and major cardiac events, although the death rate was 2- to 3-fold higher among the older patients.⁴⁴

Surgical Care

Revascularization therapies for symptomatic or ischemia-producing atherosclerotic lesions include both percutaneous approaches and open heart surgery. Long-term mortality is similar after coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) in most patient subgroups with multivessel coronary artery disease; therefore, the choice of treatment should depend on patient preferences for other outcomes. In a collaborative analysis of individual patient data from 10 randomized trials, Hlatky et al found CABG to be a superior option for patients with diabetes and patients aged 65 years or older because mortality was lower in these subgroups.⁴⁵

• Percutaneous coronary interventions
  • Percutaneous transluminal coronary angioplasty (PTCA)
  • Cutting balloon angioplasty
  • Coronary stent placement
    • Bare stents
    • Drug-eluted stents
  • Coronary atherectomy
    • Directional coronary atherectomy
    • Rotational coronary atherectomy or rotablator
    • Transluminal extraction catheter atherectomy
    • Excimer laser atherectomy
  • AngioJet suction device
  • Brachytherapy - Intracoronary radiation therapy
    • Gamma-ray devices
    • Beta-ray devices
• Coronary artery bypass surgery
  • Open heart surgery with use of bypass pump
  • Beating heart surgery
  • Keyhole or minimal incision coronary bypass
  • Bypasses using arterial conduits
• Surgical transmyocardial laser
• Percutaneous transmyocardial laser
• Ileal bypass surgery
• Miscellaneous therapies
  • Chelation therapy
    • Ethylenediaminetetraacetic acid
    • Hydrogen peroxide
  • Plethysmography/extracorporeal counterpulsation for angina pectoris

Consultations

• Cardiologists
• Cardiovascular surgeons
• Lipidologists
• Nutritionists and dietitians
• Cardiac rehabilitation team
• Radiologists

Diet

Sinha et al concluded that high intakes of red or processed meat were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality. 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.⁴⁶

The ATP III recommends a multifaceted lifestyle approach to reduce the risk for CHD. This is the TLC approach, 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 (10-25 g/d) intake
• Weight reduction
• Increased physical activity

To initiate TLC, 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 reduce triglyceride levels and 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.

Activity

Management of underlying causes of the metabolic syndrome includes the following:

• The first-line therapies for all lipid and nonlipid risk factors associated with the metabolic syndrome are weight reduction and increased physical activity, which effectively reduce all of these risk factors. Therefore, after appropriate control of LDL-C levels, TLC should stress weight reduction and physical activity if the patient has a metabolic syndrome.
• Weight control
  • In the ATP III, overweight and obesity are recognized as major underlying risk factors for CHD and are identified as direct targets of intervention. Weight reduction enhances LDL lowering and reduces all of the risk factors of the metabolic syndrome.
  • The recommended approaches for reducing weight and obesity are contained in the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults from the NHLBI Obesity Education Initiative.
• Physical activity
  • Physical inactivity is also a major underlying 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 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.
  • 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.

Medication

The goals of pharmacotherapy are to reduce morbidity and mortality and to prevent complications.

HMG-CoA reductase inhibitors

Reduce LDL-C by reducing production of mevalonic acid from HMG-CoA and stimulating LDL catabolism.

Atorvastatin (Lipitor)

Competitively inhibits HMG-CoA, which catalyzes rate-limiting step in cholesterol synthesis. Before initiating therapy, place patients on cholesterol-lowering diet for 3-6 mo, and continue diet indefinitely.

Pravastatin (Pravachol)

Competitively inhibits HMG-CoA, which catalyzes rate-limiting step in cholesterol synthesis. Before initiating therapy, place patients on cholesterol-lowering diet for 3-6 mo, and continue diet indefinitely.

Simvastatin (Zocor)

Competitively inhibits HMG-CoA, which catalyzes rate-limiting step in cholesterol synthesis. Before initiating therapy, place patients on cholesterol-lowering diet for 3-6 mo, and continue diet indefinitely.

Rosuvastatin (Crestor)

Competitively inhibits HMG-CoA, which catalyzes rate-limiting step in cholesterol synthesis. Before initiating therapy, place patients on cholesterol-lowering diet for 3-6 mo, and continue diet indefinitely.

Pitavastatin (Livalo)

HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, 2 mg/d reduced total cholesterol and LDL cholesterol similar to atorvastatin 10 mg/d and simvastatin 20 mg/d.

ACE inhibitors

Hypertension and atherosclerosis may be intimately linked through their effects on vascular endothelial dysfunction, which are mediated by the renin-angiotensin system (RAS). A-II, a potent vasoconstrictor and the principal active peptide of the RAS, can produce structural changes in the vessel wall associated with atherosclerosis. The role of RAS in the pathogenesis of atherosclerosis is supported by several lines of evidence, including the presence and up-regulation of ACE and A-II in the walls of atherosclerotic arteries.

A-II and bradykinin also regulate cellular proliferation, inflammation, and endothelial function, which are known to contribute to the pathogenesis of atherosclerosis. Clinical trials have also demonstrated that ACE inhibition improves the prognosis of patients who have (or are at risk for) atherosclerotic vascular disease, independent of its effects on left ventricular function and hypertension.

Ramipril (Altace)

Prevents conversion of A-I to A-II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Quinapril (Accupril)

Prevents conversion of A-I to A-II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Calcium channel blockers

Inhibit calcium ions from entering slow channels, select voltage-sensitive areas, or vascular smooth muscle.

Atherosclerosis is a vascular disorder characterized by abnormalities in vasoconstriction and endothelial function, ultimately leading to partial or complete vessel occlusion. Because the atherosclerotic plaque is marked by changes in calcium regulation, the potential antiatherosclerotic role for calcium antagonists has piqued interest.

Amlodipine (Norvasc)

Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery.

Platelet aggregation inhibitors

May have a positive influence on several hemorrhagic parameters and may exert protection against atherosclerosis through inhibition of platelet function and through changes in the hemorrhagic profile.

Clopidogrel (Plavix)

Selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation.

Abciximab (ReoPro)

Chimeric human-murine monoclonal antibody approved for use in elective/urgent/emergent percutaneous coronary intervention. Binds to receptor with high affinity and reduces platelet aggregation by 80% for up to 48 h following infusion. Prevents acute cardiac ischemic complications in patients with unstable angina unresponsive to conventional therapy.

Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)

Inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis.

Polyunsaturated fatty acids

Long-chain omega-3 polyunsaturated fatty acids (PUFAs) possess several properties that may positively influence vascular function. These include favorable mediator profiles (nitric oxide, eicosanoids), which influence vascular reactivity, change vascular tone via actions on selective ion channels, and maintain vascular integrity. In addition to direct effects on contractility, omega-3 PUFAs may affect vascular function and the process of atherogenesis via inhibition of vascular SMC proliferation at the gene expression level and modification of expression of inflammatory cytokinesis and adhesion molecules.

Omega-3 polyunsaturated fatty acid (Fish oil)

Possible benefits in the treatment of atherosclerosis include effects on lipoprotein metabolism, hemostatic function, platelet/vessel wall interactions, and antiarrhythmic actions; additionally, inhibition of proliferation of SMCs (and therefore growth of the atherosclerotic plaque) may occur. Ingestion of fish oil has also been found to result in moderate reductions in blood pressure and in modification of vascular neuroeffector mechanisms.

Antioxidants

Several lines of evidence suggest that antioxidants have beneficial effects with regard to cardiovascular disease. Some antioxidants have beneficial effects on cell functions that are pivotal in atherogenesis. Antioxidants may inhibit platelet aggregation and proinflammatory activity of monocytes.

Vitamin E (Aquasol E, Vitec, E-Vitamin)

Protects PUFAs in membranes from attack by free radicals and protects red blood cells against hemolysis.

Vitamins

Folates may play a role in the prevention of cardiovascular disease. Several studies have reported beneficial effects of folates on endothelial function. Observational studies have demonstrated an association between folate levels and cardiovascular morbidity and mortality. Folic acid is used for hyperhomocystinemia.

Folic acid (Folvite)

Exact mechanisms underlying ameliorative effects of folates on endothelium await elucidation; however, potential mechanisms include antioxidant actions, effects on cofactor availability, or direct interactions with enzyme endothelial nitric oxide synthase.

Hormone replacement

Several studies have suggested that impairment of vascular endothelial function is an initial step in the development of atherosclerosis. Recent studies have shown that estrogen replacement therapy improves endothelial function and reduces plasma levels of endothelin-1 in postmenopausal women at risk of CAD. Not useful in CAD prevention.

Estrogen (Premarin)

May improve endothelial function.

Antibiotics

Because inflammation is now considered an operative paradigm for atherosclerosis, some authorities hypothesize that infectious viral or bacterial agents may play a role in its pathogenesis. With the recent discovery that peptic ulcer disease—heretofore considered a disease of excess acid and reduced mucosal resistance—is caused by the ubiquitous bacterium H pylori, interest in finding an infectious etiology for atherosclerosis has increased.

Infectious agents, including C pneumoniae and H pylori, are being studied as causative factors in the pathogenesis of atherosclerosis and its manifestations, especially as they relate to CAD. The ability of certain antibiotics to penetrate cells makes them highly suitable for the treatment of diseases caused by intracellular pathogens that might be associated with the development of atherosclerosis.

Gatifloxacin (Tequin)

Quinolone that has antimicrobial activity based on ability to inhibit bacterial DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Differences in chemical structure among quinolones have resulted in altered levels of activity against different bacteria. Altered chemistry in quinolones results in toxicity differences.

• Search for CME/CE on This Topic »

• Atherosclerosis (Cardiology)
• Complications of Myocardial Infarction (Cardiology)

• Circulatory Problems Center
• Chest Pain Overview
• Heart Attack Overview
• Angina Pectoris Overview
• Cholesterol Center
• High Cholesterol Overview
• Lifestyle Cholesterol Management
• Statins Center
• Statins Overview

• CAD Hospitalizations Decline, But HF Admissions Increase

• Prevention of Coronary Heart Disease in Women
• Bivalirudin Versus Unfractionated Heparin During Percutaneous Coronary Intervention (ISAR-REACT 3)
• Clinical and Angiographic Outcomes in Diabetic Patients following Single or Multivessel Stenting in the COSTAR II Randomized Trial