(Circulation. 1997;96:1360-1362.)
© 1997 American Heart Association, Inc.
Articles |
Lipid Lowering Versus Revascularization
An Idea Whose Time (For Testing) Has Come*
From Cedars-Sinai Medical Center, Los Angeles, Calif.
Correspondence to James S. Forrester, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room 5314 North Tower, Los Angeles, CA 90048-1865. E-mail forrester{at}csmc.edu
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Abstract |
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Abstract There is strong evidence that revascularization does not prevent myocardial infarction in patients with stable coronary artery disease (CAD). The anatomic basis for this counterintuitive conclusion seems to be that most myocardial infarctions occur at sites that did not previously exhibit an angiographically significant stenosis. These angiographic observations are further supported by thallium studies in stable CAD that demonstrate that the site of stress-induced ischemia is frequently not the site of subsequent myocardial infarction. Since both coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty are directed at more severe coronary stenoses, we are led to the remarkable conclusion that angiography does not identify, and consequently revascularization therapies do not treat, the lesions that lead to myocardial infarction. The pathology of coronary atherosclerosis provides the basis for understanding why revascularization does not prevent infarction: unstable lesions that cause infarction are not necessarily severely stenotic, and stenotic lesions are not necessarily unstable. In contrast to revascularization, lipid lowering reduces the rate of myocardial infarction by
30% over a period of 5 years. Thus, we
might postulate that lipid lowering is the more effective therapy for
both prevention of acute myocardial infarction and long-term survival.
The health policy and economic implications of this viewpoint, should
it emerge in the management of coronary heart disease, are
clearly substantial. Consequently, the relative roles of lipid-lowering
therapy and revascularization, both alone and
together, must now be determined. It is an idea whose time—for
testing—has come.
Key Words: myocardial infarction • lipids • angina • atherosclerosis
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Introduction |
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TopAbstractIntroductionReferences |
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Nothing is more sad," says Arthur Koestler, "than the death of an illusion." We believe that the illusion of cardiology is that bypass or dilatation of coronary stenoses reduces the risk of myocardial infarction. In this article, we will critically analyze the data supporting this view. We will then discuss the biological basis for the dissociation between the angiographic severity of a stenosis and its propensity to become a culprit lesion. Finally, we will speculate on the implications of confronting this illusion.
Strong evidence from the CABG literature indicates that revascularization does not prevent myocardial infarction.1 2 3 4 For example, Muhlbaier et al1 reported an observational 10-year follow-up of 5428 patients with medical and surgical therapy for CAD. In the cohort with ejection fraction >0.50, the incidence of nonfatal infarction was 49% for the surgically treated patients and 41% for the medically treated cohort. Smaller differences were found in other groups stratified by ejection fraction. The mortality rates, however, favored surgery. The authors speculated that although surgery does not reduce the likelihood of infarction, it may decrease the likelihood of a fatal infarction. This speculation is consistent with the prior report of Wiseman et al,3 who compared the frequency of recurrent infarction in matched groups of 205 CAD patients treated either medically or surgically. At 5 years after discharge, the bypass patients had had more reinfarctions (40% versus 23%, P=.007), yet the cumulative mortality in the two groups was similar. Finally, in the CASS, the 3-year incidence of myocardial infarction in nonsurgical patients was 8%, whereas in the surgically treated group it was 10%.5 Consistent with the other comparative studies, however, the mortality rate for those who developed infarction was lower in the surgically treated group. Taken together, these data support the conclusion that although surgery reduces long-term mortality in some subsets, it does not reduce the incidence of myocardial infarction in patients with stable CAD.
Although PTCA reduces the rate of acute reinfarction after thrombosis, there are fewer data for determining whether PTCA prevents myocardial infarction in stable CAD patients. Nishiyama et al6 reported that the 5-year incidence of nonfatal myocardial infarction was not different between PTCA and medical therapy (2.5% versus 1.8%). Furthermore, meta-analysis of 3371 patients in eight randomized trials comparing CABG with PTCA suggests that the combined end point of cardiac death and nonfatal myocardial infarction is slightly higher in the PTCA group (risk ratio, 1.10).7 From such data, we may speculate that in stable CAD patients, PTCA is unlikely to reduce infarction rate compared with medical therapy, since neither differs from CABG in this outcome measure. Aside from one small trial that is not sufficiently powered to analyze death and infarction,8 there are no randomized trials of PTCA versus medical therapy. In the absence of such data, we may draw the conclusion that there are no data to support the belief that revascularization reduces the rate of myocardial infarction.
The anatomic basis for this counterintuitive conclusion seems to be revealed by serial angiography. Most myocardial infarctions occur at sites that did not previously exhibit a significant stenosis. Moise et al9 found that of 116 occluded coronary arteries at second angiography, 72% occurred in segments previously free of high-grade stenoses. A compilation of the published serial angiographic literature10 11 12 13 14 suggests that only 13% of the culprit lesions have >75% stenoses before myocardial infarction. Finally, Kerensky et al 15 and Little et al16 showed that in patients with stable CAD, infarcts in the month after CABG or PTCA often occur at untreated sites. After successful PTCA, 57% of the early infarctions occurred at a site that previously had an untreated, nonobstructive lesion.
The limitation of the serial angiographic data is that the culprit lesions are seldom imaged in close temporal proximity to the clinical event, so that rapid growth of a lesion just before myocardial infarction remains a possibility. By providing an image of the culprit lesion immediately after the event, postthrombolytic angiography has resolved this problem. For instance, Brown et al17 found that the average percent diameter of coronary stenosis after thrombolysis was 56%. Thus, although angiographic evidence of coronary atherosclerosis establishes a major increase in the risk of myocardial infarction, it does not necessarily indicate the site at which coronary occlusion will occur.
Before analyzing the cause of this apparent paradox and its therapeutic implications, we must add some caveats of clarification. Angiographic studies have also shown that the more obstructive a plaque is, the more frequently it progresses to coronary occlusion.18 19 20 21 In the CASS, for instance, the subsequent coronary occlusion rate was 2% for diameter stenoses of 5% to 49% and 24% for stenoses of 81% to 95%. On the other hand, because nonobstructive lesions are common and obstructive lesions are rare, the ratio of occlusions at sites with <50% diameter stenoses to those with >50% stenosis was 7.4 to 1 (2591 versus 347). Consequently, most myocardial infarctions evolve from mild to moderate stenoses. Since both CABG and PTCA are directed at more severe coronary stenoses, we are led to the remarkable conclusion that angiography does not identify, and consequently revascularization therapies do not treat, the lesions that lead to myocardial infarction.
The explanation for this second counterintuitive conclusion is found in the histology of plaques that cause myocardial infarction.22 These plaques have four distinguishing characteristics: (1) a large extracellular lipid core, (2) a thin fibrous cap, (3) inflammation (many macrophages, few smooth muscle cells), and (4) eccentric distortion of the vessel lumen.23 24 For instance, Davies et al23 found that the lipid pool exceeded 40% of plaque volume in 91% of ruptured plaques, whereas only 10% of intact plaques had lipid pools of this size. Such plaques have been identified, by both pathology and angioscopy, as the culprit lesion in 75% to 95% of acute coronary syndromes.25 26 27 This type of plaque, which is prone to disruption with subsequent formation of occlusive or subocclusive thrombus, need not be obstructive.
The mechanisms responsible for plaque destabilization and rupture of the lipid-rich plaque are both biochemical and physical. Oxidized LDL in the vessel wall stimulates expression of chemotactic factors for circulating monocytes, which enter the vessel wall. The monocytes are transformed into tissue macrophages by ingestion of LDL. Over time, the macrophages die, creating the extracellular lipid pool. After formation of a fibrous plaque over this necrotic core, activated macrophages at its margins express proteolytic enzymes that erode the fibrous cap. The lipid pool, semiliquid at body temperature, is vulnerable to physical distortion that increases the internal and external stress on the thinned fibrous cap, which, when it ruptures, can lead to formation of occlusive thrombus, causing acute myocardial infarction. Although these biochemical and physical factors are largely independent of percent diameter stenosis, the clinical impact of plaque rupture is not. Nonobstructive stenoses do not induce development of collateral vessels. For this reason, smaller plaques are more likely to cause a clinical event during thrombotic coronary occlusion because of the absence of protective collateral flow.28 Thus, the pathology of coronary atherosclerosis provides the basis for understanding why revascularization does not prevent infarction. Plaque instability causes myocardial infarction. The unstable lesions that cause infarction are not necessarily severely stenotic, and stenotic lesions are not necessarily unstable.
This distinction between the instability of a plaque and its magnitude
of stenosis extends to assessment of prognosis and selection of
therapy. The long-established angiographic practice of quantifying the
magnitude of focal stenoses and counting the number of diseased
vessels does provide prognostic information about survival, at least in
part because multivessel disease correlates with poor left
ventricular function. When left ventricular
function is normal, however, this approach is far less useful. Thus, an
unanticipated outcome in the CASS Registry was that for medically
treated patients with normal left ventricular function, the
survival curves for nonstenotic CAD and severe three-vessel
disease were indistinguishable.5 In contrast, the level of
blood lipids is a potent discriminator of long-term risk. Thus,
Pekkanen et al29 found that the 10-year risk of death in
men with established CAD increased from 4% to 20% with an increase in
the level of blood cholesterol from "desirable"
(<210 mg/dL) to "high" (>245 mg/dL). These large differences in
10-year relative risk extend to asymptomatic men, although
at a lower level of absolute risk (2% versus 5%). Recent large
population studies from the United States, Finland, and Canada have
confirmed these results.30 31 32 The clinical trial correlate
of these data is the 30% reduction in myocardial infarction over 5
years with lipid lowering.33 34 On the basis of the
observed progressive divergence of event rates between follow-up years
1 through 5 and the previously published data relating prognosis to
cholesterol levels, we may anticipate that the reduction in
the rate of myocardial infarction will be substantially greater after
10 years of lipid-lowering therapy.
One might postulate that the most effective method for reducing the frequency of acute myocardial infarction in high-risk patients is lipid-lowering therapy rather than revascularization. The diverse lines of evidence that support this hypothesis include the limited effectiveness of revascularization for preventing myocardial infarction, the now-established causal role of plaque instability in acute infarction, and the recent randomized clinical trial results of lipid-lowering therapy that report long-term reduction in cardiac events. The health policy and economic implications of this viewpoint, should it be proven correct in the management of coronary heart disease, are clearly substantial. Unfortunately, the history of cardiovascular therapy has innumerable examples of ideas that were compellingly logical but wrong. Consequently, the relative roles of lipid-lowering therapy and revascularization, both alone and together, must now be determined. It is an idea whose time (for testing) has come.
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Selected Abbreviations and Acronyms |
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Footnotes |
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1 In 1974, just before the thrombolytic era, Drs Eugene Braunwald and P.R. Maroko wrote a seminal editorial entitled "The Reduction of Infarct Size: An Idea Whose Time (For Testing) Has Come" (Circulation. 1974;50:206-209). The article influenced the thoughts of many young investigators of that era. We have chosen to paraphrase Braunwald and Maroko's provocative title.
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References |
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TopAbstractIntroductionReferences |
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