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The Importance of Lipid Evaluation and Management in the Prevention and Treatment of Acute Myocardial Infarction

from Preventive Cardiology
Posted 08/16/2002
Monte Malach, MD; Pascal James Imperato, MD, MPH & TM

Abstract and Introduction
There is an obvious need to measure low-density lipoprotein cholesterol in all patients with acute myocardial infarction and coronary artery disease. The recent guidelines of the National Cholesterol Education Program have established the desired level for low-density lipoprotein cholesterol for such patients at <100 mg/dL. However, several studies have demonstrated a lack of low-density lipoprotein cholesterol measurement and lipid-lowering therapy with statins in patients with acute myocardial infarction and coronary artery disease. These findings point to a need for quality of care improvement efforts to foster both lipid measurement and statin use in such patients. Many studies have demonstrated the numerous beneficial effects of statin use. In addition to lipid lowering, these include plaque stability and antiplatelet, antimacrophage, and antiatherothrombotic activities as well as enhanced endothelial activity. As a class of drugs, the statins have been shown to offer significant benefits with little in the way of associated risks.

There are five components to early, aggressive therapy for the treatment of acute myocardial infarction (AMI). These include aspirin, blockers, and "clot busters" -- reperfusion by thrombolytics or primary angioplasty (ABC),[1] angiotensin-converting enzyme (ACE) inhibitors for congestive heart failure (CHF) or any large anterior AMI,[2] and now lipid-lowering therapy (LLT).

The benefits of ABC on morbidity, mortality, and recurrent events at 30 days and 1 year are impressive. It has been found that aggressive therapeutic intervention within 12-24 hours with aspirin and blockers in the emergency room and 30-minute door-to-needle time for thrombolysis are workable and extremely effective, as noted in the Guidelines for the Management of Patients with Acute Myocardial Infarction issued by the American College of Cardiology/American Heart Association.[2] Primary angioplasty for AMI has increasingly been adopted as the intervention of choice at a growing number of large medical centers.[3] The suggestion of fewer hemorrhagic strokes in angioplasty patients than in patients treated with thrombolytics also makes it an attractive choice.[4]

The report of the Heart Outcomes Prevention Evaluation (HOPE) study[5] drew attention to the protective benefit of the ACE inhibitor ramipril in patients with AMI without CHF. This study demonstrated that its use resulted in a 22% decrease in death and stroke. Previous reports have indicated the favorable effect of ACE inhibitors on remodeling of the newly infarcted wall, thus yielding a less flabby myocardium and a smaller heart in patients with an ejection fraction <40%.[2]

The fifth therapeutic modality for patients with AMI is the use of statins for LLT. In addition to an absolute reduction in fatal AMI and recurrent events, there is significant prevention of initial events. This report focuses on the use of statins as early LLT in patients with AMI and coronary artery disease (CAD).

Lipid Levels As Risk Factors
Public awareness of the connection between cholesterol, lipids, and CAD has increased dramatically in recent years,[6] and in particular because of the updated report of the National Cholesterol Education Program (NCEP).[7] A major focus of the NCEP report is on low-density lipoprotein cholesterol (LDL-C), which is the primary target of therapy. LDL-C has also been the focus of major clinical trials, and " a result, the primary goal of therapy and the cut points for initiating treatment are stated in terms of LDL."[7] Indeed, the outcome benefits in terms of morbidity and mortality in CAD are related to the reduction of LDL-C. Frequently, there are also concomitant decreases in total cholesterol (TC) levels and modest elevations of high-density lipoprotein (HDL) levels.

Currently, optimal levels for LDL have been set at <100 mg/dL, while those for TC and HDL have been set at <200 mg/dL and >60 mg/dL, respectively. Risk assessment has been based on a history of CAD, family history of CAD, diabetes (now considered the risk equivalent of existing CAD), hypertension, cigarette smoking, HDL <40, LDL >160, men >/=age 45 and women, >/=age 55. Multiple risk factors increase the need to lower LDL to <100.

Need for Increased Measurement of LDL-C
In addition to recognizing risk factors, there is also a need to increase measurement of LDL-C. Three recently published studies have focused on this issue,[8-10] and two of them have demonstrated inadequate lipid measurement in patients hospitalized with AMI.

A study undertaken by IPRO, the federally funded quality improvement organization (QIO) for New York State, demonstrated serious in-hospital deficiencies in simply ordering lipid levels on Medicare patients with AMI.[8] In this study, 20 hospitals participated in a collaborative quality improvement effort. The baseline data consisted of rates of lipid level measurement, dietary counseling, and LLT for 406 hospitalized Medicare patients with documented AMI. The intervention consisted of forming multidisciplinary teams within hospitals (medicine, nursing, laboratory, pharmacy, and social service) in order to identify gaps in the process and needed modifications, with a focus on accomplishing uniform ordering of lipid levels on admission or during hospitalization. Educational meetings, site visits, and teleconference calls were conducted with team leaders and hospital opinion leaders, who were also provided with the recent relevant medical literature. A provider user-friendly protocol and a written plan were also requested from each hospital.

Postintervention data demonstrated much improved LDL-C measurement on admission to the hospital, from a baseline of 32/406 (8%) to 161/498 (32%), and LDL-C measurement during hospitalization from a baseline of 57/406 (14%) to 241/498 (48%) (p<0.001). In addition, the prescribing of LLT for LDL-C >130 mg/dL rose from 0 to 22/48 (46%) (p<0.001). Dietary intervention was unchanged, from 204 (50%) to 245 (49%) of the patients. The inclusion of LDL-C on admission blood specimen panels was both a goal and an achievement. The results of this study indicate that a focused, user-friendly method, protocol, or preprinted order sheet can enhance the ordering of LDL-C and LLT for elevated LDL-C. While there was significant improvement as a result of this quality improvement intervention, performance levels are still well below the ideal in terms of LLT.

The National Registry of Myocardial Infarction (NRMI) study involved a national sample of 138,001 patients with AMI in 1470 US hospitals.[9] It showed that LLT was ordered on discharge from the hospital in only 37.7% of patients. This is a disturbing finding, in view of the dramatic benefits of early statin therapy on morbidity, mortality, and recurrent events requiring rehospitalization and the existence of readily available guidelines.

The Cardiac Hospitalization Atherosclerosis Management Program (CHAMP) study undertook improvement in initiating medical therapy in patients discharged after AMI.[10] The increase in statin use rose from 6% to 86%, LDL levels were reduced to <100 mg/dL in 58% vs. a baseline of 6%, and there was a significant reduction in 1-year mortality. There was also concomitant significant improvement in the use of aspirin, blockers, and ACE inhibitors as a result of a program to increase the use of all of these medications prior to hospital discharge.

The three cited studies demonstrate that physicians are failing to order lipid levels on admission for an AMI and that LLT is not ordered for the majority of patients with AMI. Yet the role of statins in LLT has clearly been demonstrated for primary and secondary prevention of CAD, as well as stroke prevention. Thus, there is a need to utilize techniques that not only increase the regular measurement of LDL-C but also initiate LLT during hospitalization for AMI or CAD.

Primary Prevention
Increasing numbers of large, randomized, controlled clinical trials have demonstrated the value of LLT in high-risk patients with or without symptoms.[11,12] The Lipid Research Clinics Program-Coronary Primary Prevention Trial (LRC-CPPT), published in 1984,[13] reported on the use of cholestyramine. It was found that in 3806 men with hypercholesterolemia who were followed for 7 years, the drug reduced TC by 13.4%, LDL-C by 20.3%, and CAD events by 19%. Another primary prevention trial using the fibrate gemfibrozil in 4081 asymptomatic men with elevated lipid levels demonstrated a 34% decrease in CAD events during a 5-year follow-up.[14]

In the West of Scotland Coronary Prevention Study (WOSCOPS), reported in 1995,[15] 6595 men <65 years of age with no history of myocardial infarction (MI) and elevated TC were treated with pravastatin over a 4.9-year follow-up. There were reductions of 33% in CAD deaths, 22% in all-cause mortality, and 11% in strokes, associated with a decrease in TC of 20% and LDL-C of 26%.

Another primary prevention trial was the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), which involved 6605 individuals, amongst which were 997 women and 1416 people aged 65-73, who were at low to average risk and had average LDL-C and TC levels. The statin (lovastatin) was given for 5+ years and reduced LDL-C by 25% and first CAD event or death by 36%.[16]

Secondary Prevention
Many providers have historically paid little attention to the lipid levels of older patients, based on a now-dated belief that intervention would not affect either cardiovascular morbidity or mortality.[17] The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) study, published in 1995,[18] involved 9014 patients aged 65-75 years with known CAD and normal or only slightly elevated TC. There were decreases in mortality (24%), all cause-mortality (22%), and stroke (19%). LDL-C decreased 25% among the treatment group. An updated review of the LIPID study, published in 2001,[19] focused on patients up to age 80 and found the absolute benefit of treatment to be significantly greater in older patients as a form of secondary prevention.[20] It has thus been suggested that high levels of LDL-C may cause CAD in the absence of other risk factors in the elderly.

The Cholesterol and Recurrent Events (CARE) trial found that in 1283 older patients (65-75 years) with an AMI and TC and LDL levels in the average range (<240 mg/dL and 115-174 mg/dL, respectively), pravastatin (40 mg/day) reduced major coronary events.[21] These events occurred in 28.1% of the placebo group and in 19.7% of the pravastatin group. Stroke incidence was 7.3% in the placebo group vs. 4.5% in the pravastatin group. About 75% of deaths from AMI occurred in patients over age 65, the group that has been less likely to receive statin therapy.[21]

The Scandinavian Simvastatin Survival Study (4S), published in 1994,[22] involved 4444 high-risk men and women (827) and included a 5-year follow-up. All of the individuals, who were recruited from 94 clinical centers, had angina or a prior AMI and hypercholesterolemia, and were placed on a lipid-lowering diet and randomized to simvastatin or placebo. There were reductions in all-cause mortality (30%), CAD deaths (42%), stroke (30%), TC (28%), and LDL-C (35%). The conclusion of the investigators was that the drug was effective and safe. Of interest, there were seven violent deaths in the placebo group and six in the drug group. One case of rhabdomyolysis occurred in a patient taking 20 mg/day of simvastatin, with recovery after discontinuance of the drug. Six patients had a 10-fold creatine phosphokinase elevation on the drug; 20 had alanine aminotransferase and 49 aspartate aminotransferase elevations, without muscle symptoms.

A Canadian study[23] compared the use of statin LLT in 42,628 elderly patients (>/=65 years) after AMI, both before and after publication of the 4S study. They found a 3.6-fold increase in statin use after the 4S study. Cardiologists and internists increased their use of statins twice as much as general physicians.

Aggressive LLT was compared with angioplasty in patients with stable CAD and LDL-C of at least 115 mg/dL in the Atorvastatin Versus Revascularization Treatment (AVERT) study.[24] During an 18-month period, atorvastatin, 80 mg daily, reduced the incidence of ischemic events by 36%. The patients on atorvastatin also had a significantly longer time to a subsequent ischemic event.

There has been an extension of LLT to acute coronary syndromes, which now include unstable angina and non-Q wave MI. Thirty-day mortality rates, with or without LLT, were 0.5% and 1.0%, respectively, and 6-month mortality rates were 1.7% and 3.5%, respectively.[25]

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial was a randomized clinical trial that assessed the benefit of early, high-dose (80 mg/day) atorvastatin initiated within 24-72 hours of an acute coronary syndrome or unstable angina in 3086 patients in 122 clinical centers. It was found that atorvastatin reduced recurrent symptomatic ischemia requiring emergency hospitalization by 16% in a 16-week follow-up.[26] Also, there were only 12 strokes in the atorvastatin group, compared to 24 in the nontreatment group. While this was a very short-term study, the implications strongly point to a decrease in subsequent clinical cardiac events.

The early implementation of statin treatment in patients with AMI in the Swedish Registry of Cardiac Intensive Care[27] resulted in a significant reduction in 1-year mortality. After adjusting for other risk factors, there was a relative risk reduction of 20% in favor of the statin-treated patients. This was evident regardless of age, sex, prior disease manifestation, or medications. This study involved 137,262 admissions to 58 coronary care units of unselected survivors of a documented AMI from 1995-1998. The conclusion from the foregoing trials is that a statin should not only be given, but started as soon as possible after an AMI or acute coronary syndrome.

The progression of CAD has reportedly been brought to a standstill with the combination of simvastatin and niacin, both of which raise HDL and lower LDL.[28] Despite concern about the side effects of niacin, 90% of patients remained on combination therapy at the end of 3 years. In addition, there was a 70% reduction in clinical events at 3 years from combined therapy, compared to a 35% reduction on simvastatin alone. HDL increased 30% above baseline with combination therapy, as opposed to 10% on a statin alone.

Other Benefits of Statins
Other significant actions of statins merit attention because of marked benefits in coronary and cerebrovascular disease that may be related to the non-lipid-lowering effects of these drugs. Plaque stability is probably an equal or greater benefit of statin use by virtue of prevention of macrophage activity at the site of lipid-filled atheromas.[29] This action may prevent acute occlusion of vessels where there may be little or no actual luminal narrowing, but unstable intramural atheromas. In a study of 42 patients who had coronary arteriography before or up to 1 month after an AMI, it was found that there was stenosis of 50% or less in the affected vessel.[30] Another study revealed that AMI frequently developed in myocardium perfused by arteries with noncritical stenosis.[31] Thus, a vulnerable plaque in a vessel without a high-grade stenosis may produce an acute event. This may be preventable by statin-induced plaque stabilization and antimacrophage activity.

Plaque disruption is a macrophage-dependent process.[29] Macrophages are attracted to the atheroma, causing the release of metalloproteinases, which lyse the thin, fibrous cap of atheromas, resulting in an occluded blood vessel that promotes thrombosis. Hypercholesterolemia has been shown to be associated with increased platelet-dependent thrombosis generation. Pravastatin has been shown to normalize the generation of thrombin.[32] As a supplement to the effect of statins on macrophages, it has been demonstrated that long-term exercise also decreases the atherogenic activity of the blood mononuclear cells in persons at high risk of developing ischemic heart disease.[33]

Statins also have antiplatelet activity. Patients with elevated LDL-C have platelets that are also more sensitive to aggregation than patients who have normal LDL-C or TC levels. Simvastatin and pravastatin have both been shown to reduce platelet aggregation. Statins also maintain a favorable balance between prothrombotic and fibrolytic mechanisms, resulting in a decrease of coronary artery thrombosis.[34] Indeed, the membrane cholesterol content of platelets is reduced by pravastatin, which alters platelet membrane fluidity, thus making platelets less likely to provoke thrombosis.[34,35]

The antithrombotic actions of statins are multifactorial. They include reversal of blood hypercoagulability by reduction of oxidized LDL-C, improved blood flow, decreased vasospasm, improved endothelial function, improved fibrinolysis, and plaque stability.[35] Statins reduce the progression of carotid intima-media thickening. In addition, statin-enhanced plaque stability has also been reported in the carotid arteries.[35] Retardation of carotid artery plaque formation has been shown to result from the use of blockers, ACE inhibitors, and calcium channel blockers.[36] In peripheral artery disease, among 11 atherothrombotic biomarkers assessed at baseline, TC, HDL-C, and C-reactive protein (CRP) were found to be the strongest predictors of the development and prognosis of peripheral arterial disease.[37]

Pravastatin has been shown to improve endothelial activity by limiting acetylcholine-induced vasoconstriction. It thereby inhibits stasis-induced increases in thrombosis and spasm and promotes vasodilatation and antithrombosis. Up-regulation of nitric oxide synthesis by statins preserves nitric oxide, which inhibits macrophage and platelet adhesion and thereby maintains thrombosis resistance on the endothelial wall. Oxidized LDL inhibits nitric oxide. Statins reduce oxidation of LDL, thus enhancing an active endothelium.[29,35] This is a mechanism whereby statins decrease acute obstructive coronary and carotid artery disease, AMI, and stroke. A study by Raitakari et al.[38] demonstrated that oxidized LDL in high concentration exhibits injurious effects on the coronary vascular bed.

Further evidence that statins may enhance circulation is that vasospasm is decreased, as shown by improved forearm blood flow in hypercholesterolemic patients treated with statins for 4 weeks.[39] In addition, LDL apheresis increases forearm blood flow. After 3 months of statin therapy, coronary artery perfusion increases, which conceivably is related to decreased vasospasm in addition to regression of plaques.[35]

Stroke prevention is a clear benefit of statin use, and studies support the role of lowered blood lipids in the prevention of subsequent stroke and transient ischemic attack in patients with established CAD.[40] There is growing evidence for the reversal of carotid artery thickening and unstable plaques. It was shown that pravastatin reduced the incidence of stroke by 11% in the WOSCOPS study,[15] 31% in the CARE study,[18] and 19% in the LIPID study.[21] The 4S study demonstrated a 30% reduction of stroke with simvastatin.[22]

There are increasing suggestions that atherosclerosis is an inflammatory process.[41,42] Elevation of CRP has been demonstrated in unstable angina and non-Q wave MI. The Pravastatin Inflammation/CRP Evaluation (PRINCE) study[43] evaluated the effect of pravastatin on CRP as a marker for coronary artery disease and atherosclerosis. Pravastatin lowered CRP, TC, and LDL-C within 12 weeks of treatment. As further enhancement of the concept that atherosclerosis is an inflammatory process, it has been reported that lovastatin therapy reduces CRP, an acute-phase reactant, in patients with relatively low lipid levels.[44] Thus the primary prevention of CAD events may require CRP measurement in addition to that of lipids. As a caution, it should be noted that statins do not reduce all acute-phase reactants; since fibrinogen and plasminogen activator inhibitor type 1 are unaffected.[45] In addition, an immunomodulating benefit of statins unrelated to lipid lowering has been noted after cardiac transplantation, along with improved survival.[46]

The evidence linking the above factors to CAD is discussed in a recent review by Mawhorter and Lauer.[47] By the process of recruitment and attraction of macrophages into the intima of coronary arteries in the presence of oxidized LDL-C, these macrophages become foam cells and are the basis of an atheroma. The association of infection and seropositivity with certain specific organisms -- Chlamydia pneumoniae, cytomegalovirus, Helicobacter pylori, Coxsackie B virus, herpes virus, and others -- can transform infected monocytes into foam cells, and this may be documented by seropositivity.[36] Many trials are underway in patients with CAD to evaluate the benefit, if any, of antibiotic therapy.[47]

The standard risk factors for atherosclerosis and CAD include hyperlipidemia, hypertension, diabetes, smoking, and family history. Aside from the conventional risk factors for the development of atherosclerosis, other factors have emerged: homocysteine, fibrinogen, impaired fibrinolysis, increased platelet reactivity, hypercoagulable states, and possibly infectious and inflammatory markers (CRP).[41]

The multifactorial effects of statins, in addition to lipid lowering, all speak to the benefits of these drugs in preventing new and recurrent CAD and stroke. In Great Britain, The National Institute of Clinical Evidence has endorsed the widespread use of statins for patients who have had an AMI.[48] The new NCEP Guidelines suggest the same.[7] As stated by LaRosa et al.,[49] after a careful meta-analysis, "...the cholesterol controversy is no more." Indeed, in another study, the reduction of LDL-C with statin therapy decreased the risk of CAD and all-cause mortality for men, women, the elderly, and the middle-aged.[27]
Comparative Efficacy of Statins
It seems certain that the effects of statins are a drug class effect. Long-term studies have shown that pravastatin, simvastatin, and atorvastatin are all effective for the primary and secondary prevention of CAD events. They all show relative equivalency of effect in different doses in the long term.

The Comparative Dose Efficacy Study of Atorvastatin Versus Simvastatin, Pravastatin, Lovastatin, and Fluvastatin in Patients With Hypercholesterolemia (CURVES)[50] compared dose-related efficacy of the four agents in 518 patients. Milligram for milligram, atorvastatin proved to be most potent. All of the drugs had similar tolerability, and no instances of persistent elevation of serum transaminase or myositis were noted.

The safety and effectiveness of simvastatin in achieving United States and European guideline LDL-C levels was reported in the GOALLS Study in patients with established CAD.[51] The pharmacokinetic properties of statins, however, do vary. As reported by Bottoroff and Hansten,[52] lovastatin, simvastatin, atorvastatin, and cerivastatin are chiefly metabolized by CYP3A4. This has the potential of side effects that are more toxic and increased blood levels when combined with diltiazem, erythromycin, clarithromycin, itraconazole, ketoconazole, cyclosporine, nefazodone, and many human immunodeficiency virus protease inhibitors.[53] In patients on simvastatin and lovastatin, which are lipophilic agents, myotoxic effects are more likely to occur, including rhabdomyolysis.[51] However, this is rare when the drugs are administered as monotherapy. Pravastatin is not primarily metabolized by CYP3A4 and causes no concern with coadministered drugs metabolized by this pathway.[52]

The concomitant administration of lovastatin, simvastatin, or fluvastatin with oral anticoagulants may increase hypoprothrombinemia and the risk of bleeding. According to a Medical Letter report,[53] there was no increase in the incidence of breast cancer after 6 years of treatment. After 7 years of follow-up of patients treated with lovastatin, pravastatin, and simvastatin, there was no increase in the overall incidence of cancer.

The Future
The enticing possibility of identifying vulnerable plaques in coronary, carotid, and cerebral vessels represents the new horizon in preventive cardiology. A 360 side-view spectroscopic catheter to monitor the metabolic activity of an atherosclerotic plaque, and the detection of atherosclerotic vulnerable plaque using super paramagnetic iron oxide contrast medium, are under study.[54,55] Plaques that are both hot and acidic are considered to be more vulnerable to rupture.[56] These plaques may create no more than a 30%-50% vessel narrowing or, being in the vessel wall, may leave the vessel lumen open. It is the hot plaque that is filled with active macrophages that release metalloproteinase enzymes, which can erode the thin, fibrous cap, releasing the lipid-laden atheroma and causing occlusion and thrombosis. The addition of new techniques to the benefits of statin use for atherosclerosis permits an optimistic view for the prevention, early diagnosis, and treatment of this disease.
Current therapy for AMI requires the early, aggressive use of five specific therapies. These include: 1) aspirin; 2) a blocker in the first 12-24 hours; 3) clot buster therapy (a thrombolytic in <30 minutes or angioplasty in <90 minutes); 4) an ACE inhibitor for CHF with an ejection fraction of <40%; and 5) early statin therapy.

Although the use of statins after AMI has increased since the publication of primary and secondary prevention trials, much more education needs to be undertaken to optimize their use.

Very early statin treatment of patients with AMI and CAD has been shown to reduce both early and late morbidity and mortality. Early statin treatment is not limited by gender or age.

Governmental agencies in the United States (NCEP) and Great Britain (National Institute of Clinical Evidence) now advocate statin therapy for AMI.

The relative safety of statins has been demonstrated in all of the clinical trials. Early monitoring of liver enzymes and muscle pain is still necessary.

Studies clearly show that a majority of patients who would greatly benefit from statin treatment do not even have their blood lipids measured, much less receive early prescription of the medication.

The medical challenge is both early measurement of lipids and early treatment of patients when indicated.

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