Correspondence
Aggressive Lipid-Lowering Therapy Compared with Angioplasty in Stable Coronary Artery Disease
N Engl J Med 1999; 341:1853-1855December 9, 1999
- Article
To the Editor:
We would like to call attention to two critical limitations of the Atorvastatin versus Revascularization Treatment (AVERT) study (July 8 issue).1 First, we take exception to the authors' conclusion that “aggressive lowering of LDL [low-density lipoprotein] cholesterol levels . . . is at least as effective as angioplasty . . . in reducing the incidence of ischemic events in low-risk patients.” This statement implies that angioplasty is an effective means of reducing ischemic events in this target population. In fact, the results of previous controlled clinical trials suggest exactly the opposite.2,3 In the Angioplasty Compared to Medicine (ACME) trial, the six-month incidence of death, myocardial infarction, or repeated revascularization was 21 percent in the group assigned to percutaneous transluminal coronary angioplasty (PTCA) as compared with 14 percent in the medical-therapy group (relative risk, 1.5; 95 percent confidence interval, 0.9 to 2.1). Similarly, in the second Randomized Intervention Treatment of Angina (RITA-2) trial, the three-year cumulative incidence of death or nonfatal myocardial infarction was 6.3 percent in the PTCA group as compared with 3.3 percent in the medical-therapy group (relative risk, 1.9; 95 percent confidence interval, 1.1 to 3.4). The selection of a PTCA-based strategy as the control therapy in patients with minimal (if any) myocardial ischemia would thus seem to be a straw man that inherently biased the study toward a positive result for medical therapy, with or without aggressive lipid lowering.
Furthermore, the authors claim that restenosis was responsible for only a “small percentage of the events” between 6 and 18 months in the angioplasty group. Close inspection of the Kaplan–Meier curves (Figure 2 of the article), however, indicates that the main divergence in the curves occurred between six and eight months, an interval that is entirely compatible with the time course of clinical restenosis — particularly after coronary stenting. In fact, in the Stent Anticoagulation Restenosis Study,4 50 percent of the ischemic events due to restenosis occurred between 6 and 12 months after stenting. Thus, considering the known time course of coronary restenosis and in the absence of published data from an independent, core angiographic laboratory, attribution of the excess of ischemic events in the PTCA group to anything but restenosis seems highly implausible.
In summary, catheter-based percutaneous coronary intervention is a safe and effective means of controlling symptoms of ischemia in patients with one- or two-vessel disease, and aggressive lipid lowering is an effective means of stabilizing and reducing the progression of plaque. The fact that PTCA had little benefit in the AVERT study relates mainly to the selection of a patient population that had very little to gain from revascularization rather than to any specific benefit of lipid-lowering treatment. These therapies should thus be seen as additive and complementary5 rather than as mutually exclusive approaches, as the authors suggest.
5 ReferencesDavid J. Cohen, M.D.
Joseph P. Carrozza, M.D.
Donald S. Baim, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 022151
Pitt B ,Waters D ,Brown WV , et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70-76
Full Text | Web of Science | Medline2
Parisi AF ,Folland ED ,Hartigan P . A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. N Engl J Med 1992;326:10-16
Full Text | Web of Science | Medline3
RITA-2 Trial Participants
CrossRef | Web of Science | Medline4
Leon MB ,Baim DS ,Popma JJ , et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998;339:1665-1671
Full Text | Web of Science | Medline5
Pearson T ,Rapaport E ,Criqui M , et al. Optimal risk factor management in the patient after coronary revascularization. Circulation 1994;90:3125-3133
Web of Science | Medline
To the Editor:
The AVERT study represents the only published trial aimed at demonstrating the clinical benefit of atorvastatin in patients with coronary artery disease. However, the study failed to address its stated purpose: to evaluate whether high-dose atorvastatin benefits stable patients with one- or two-vessel coronary artery disease and normal ventricular function to a greater degree than initial management with PTCA.
Simply stated, the study used outdated PTCA techniques teamed with substandard medical care instead of a control group. Despite trials demonstrating the short-term and long-term (one-to-three-year) benefits of intracoronary stenting1,2 and platelet glycoprotein IIb/IIIa receptor blockade,3 these therapies were used in a small proportion of patients. Today, PTCA is rarely performed without one or both of these adjuvants. In addition, the patients undergoing PTCA in this study had LDL levels that were 20 percent higher than established target levels.4 PTCA does not preclude aggressive lipid management. If the authors had sought to define the role of high-dose atorvastatin in secondary prevention, a control group of patients receiving statin therapy, with the dose adjusted to achieve target LDL levels, should have been studied.
4 ReferencesMark J. Ricciardi, M.D.
Charles J. Davidson, M.D.
Northwestern University Medical School, Chicago, IL 606111
Macaya C ,Serruys PW ,Ruygrok P , et al. Continued benefit of coronary stenting versus balloon angioplasty: one-year clinical follow-up of Benestent trial. J Am Coll Cardiol 1996;27:255-261
CrossRef | Web of Science | Medline2
EPILOG Investigators
Full Text | Web of Science | Medline3
The EPISTENT Investigators
Web of Science | Medline4
27th Bethesda Conference: Matching the intensity of risk factor management with the hazard for coronary disease events, September 14-15, 1995J Am Coll Cardiol 1996;27:957-1047
CrossRef | Web of Science | Medline
To the Editor:
In the AVERT study, Pitt et al. successfully demonstrated the efficacy of aggressive lipid-lowering therapy with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin in reducing cardiac ischemic events; however, there were considerable practical limitations in their study design that deserve discussion. Specifically, the benefits of statin therapy may have been exaggerated by the use of less-than-standard medical therapy. For example, less than 70 percent of the patients in the study received beta-adrenergic antagonists, an important therapy for angina and coronary artery disease. More important, less than 50 percent received antiplatelet therapy, an effective preventive therapy against cardiac events for patients with angina.1 In addition, statins have antithrombotic effects2; therefore, the lack of aspirin use may have exaggerated the benefit of atorvastatin in this study, as it may have in previous studies of statins.3
3 ReferencesJeffrey M. Bloom, M.D.
Central Coast Primary Care, San Luis Obispo, CA 934011
Antiplatelet Trialists' Collaboration
CrossRef | Web of Science2
Rosenson RS ,Tangney CC . Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998;279:1643-1650
CrossRef | Web of Science | Medline3
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Cohen and colleagues point out that angioplasty is not an effective means of reducing ischemic events in the group of patients in the AVERT study who had clinically significant coronary artery disease but preserved left ventricular function and moderate exercise tolerance. We agree. Although 16 percent of the patients in the study were asymptomatic at the time of randomization, the majority had class I or class II angina according to the criteria of the Canadian Cardiovascular Society. An analysis of the subgroup of patients with a positive exercise test with electrocardiographic monitoring that was reported elsewhere1 demonstrated an even greater benefit among those randomly assigned to intensive lipid-lowering treatment. We do not believe that the patients in the AVERT study represented a straw man, because many patients undergoing angioplasty, at least in the United States, appear to be similar to those included in this trial.
In regard to the suggestion that the divergence in our event curves between six and eight months suggested clinical restenosis: we analyzed the angiograms during follow-up and found that the majority of events after six months were related to coronary stenosis at another angiographic site and not to restenosis. Perhaps because coronary angiography was discouraged during follow-up in the absence of worsening symptoms, restenosis was detected in only 18 of 177 patients in the angioplasty-plus-usual-care group. Seven of the 18 also had progression of another coronary lesion, which may have accounted for their clinical event. We also agree with Dr. Cohen and colleagues that patients similar to those included in the AVERT trial have “very little to gain from revascularization” and that aggressive lipid lowering is complementary to angioplasty. Unfortunately, currently available data do not support the argument that serum cholesterol is measured and effectively treated in patients undergoing angioplasty.
Drs. Ricciardi and Davidson point out that only a minority of patients in the AVERT trial received a stent. We have analyzed the 30 percent of lesions stented, and although the difference in efficacy between aggressive lipid lowering and angioplasty was less in this group there was still a trend favoring atorvastatin (18 percent vs. 16 percent). More than 70 percent of the patients in the angioplasty group received statin therapy. They did not, however, reach target LDL cholesterol levels. We agree that reducing LDL cholesterol levels below target levels should be achieved in almost every case. A trial comparing aggressive lipid lowering alone with aggressive lipid lowering plus angioplasty is being carried out but does not detract from the importance of the findings of the AVERT study for current practice in which aggressive lipid lowering to target levels is often not achieved, either in medically treated patients or in those undergoing angioplasty.
Dr. Bloom pointed out that patients in the angioplasty group received less than optimal medical therapy, which may have exaggerated the benefits of aggressive lipid lowering. Again, we agree; we recommend that all patients with ischemic disease be treated with optimal medical therapy, regardless of whether they undergo angioplasty. As pointed out above, this is a desirable goal but does not yet appear to be standard practice.
1 ReferencesBertram Pitt, M.D.
University of Michigan School of Medicine, Ann Arbor, MI 48109-0366David Waters, M.D.
Hartford Hospital, Hartford, CT 06102-5037William Virgil Brown, M.D.
Emory University School of Medicine, Atlanta, GA 30322- Citing Articles (3)
Citing Articles
1
Jean-Louis Gayet, Franck Paganelli, Alain Cohen-Solal. (2011) Update on the medical treatment of stable angina. Archives of Cardiovascular Diseases 104:10, 536-544
CrossRef2
Harinder S. Malhotra, Karen L. Goa. (2001) Atorvastatin. Drugs 61:12, 1835-1881
CrossRef3
Richard E. Katholi, Cynthia L. Deitrick, Kathy J. Hardiek. (2001) If LDL-C Is the Answer??? What Was the Question?. Heart Disease2-13
CrossRef
