Correspondence
Therapies for Type 2 Diabetes and Coronary Artery Disease
N Engl J Med 2009; 361:1407-1410October 1, 2009
- Article
To the Editor:
In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial (ClinicalTrials.gov number, NCT00006305) reported on by Frye and colleagues (June 11 issue),1 patient inclusion was based on a coronary anatomy that was suitable for revascularization. Thus, the results of this study are difficult to translate into clinical practice.
When evaluating a patient with chronic coronary artery disease, doctors must choose their strategy before catheterization. They may choose immediate catheterization with revascularization, if feasible (revascularization may not be suitable because of disease that is too diffuse or without relevant obstructions, as in the Trial of Invasive versus Medical Therapy in Elderly Patients [TIME] study2), combined with drug therapy. Another choice is initial medical management with revascularization only if drug therapy fails; this was necessary in 42% of the patients in the BARI 2D trial.
Thus, it comes as no surprise that the outcomes did not differ according to strategy in the BARI 2D trial. In fact, in several randomized, controlled trials of treatment for chronic coronary artery disease,2-4 patients with clinically important angina, ischemia, or both benefited from revascularization. Among patients with severe symptoms and ischemia,4,5 even long-term survival was improved.
Outcomes of BARI 2D in patients with ischemia are eagerly awaited, since ischemia was also a powerful factor in risk stratification in a Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) substudy (NCT00007657). The conclusion from BARI 2D, then, might be that patients with clinically important angina, ischemia, or both benefit from invasive treatment; this is a clinically relevant message.
5 ReferencesMatthias E. Pfisterer, M.D.
Michael J. Zellweger, M.D.
University Hospital Basel, Basel, Switzerland
mpfisterer@uhbs.ch 1
The BARI 2D Study Group
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The TIME Investigators
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Boden WE ,O'Rourke RA ,Teo KK , et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-1516
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Erne P ,Schoenenberger AW ,Burckhardt D , et al. Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISSI II randomized controlled trial. JAMA 2007;297:1985-1991
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Pfisterer ME . Long-term outcome in elderly patients with chronic angina managed invasively versus by optimized medical therapy: four-year follow-up of the randomized Trial of Invasive versus Medical therapy in Elderly patients (TIME). Circulation 2004;110:1213-1218
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To the Editor:
The design of BARI 2D, in which the choice of coronary-artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) was based on physician preference, precludes a comparison of outcomes according to the type of revascularization. We were therefore disappointed to read the conclusion of Boden and Taggart in the editorial accompanying the article that “When revascularization is indicated, both BARI 2D and other studies support the use of CABG as the preferred approach.”1 This conclusion is simply not true, in our view — BARI 2D showed no survival advantage over medical therapy among patients judged to be best suited for CABG.
The only completed randomized comparison of CABG with PCI in patients with diabetes, the small Coronary Artery Revascularization in Diabetes (CARDIA) trial, showed no advantage associated with CABG.2 We await completion of the larger Future Revascularization Evaluation in Patients with Diabetes Mellitus — Optimal Management of Multivessel Disease (FREEDOM) trial (ClinicalTrials.gov number, NCT00086450).3
The only fair remark about the comparison of revascularization treatments in BARI 2D is this: CABG and PCI appear to be equally limited in their ability to reduce the risk of death among patients with diabetes and coronary artery disease, even when the extent of the disease suggests that CABG, rather than PCI, should be performed.
Kirk N. Garratt, M.D.
Lenox Hill Heart and Vascular Institute of New York, New York, NY
kgarratt@lenoxhill.net Steven R. Bailey, M.D.
University of Texas Health Sciences Center at San Antonio, San Antonio, TXDr. Garratt reports receiving lecture fees from Boston Scientific, Medtronic, Sanofi-Aventis, and the Medicines Company and research support from Medtronic and Schering-Plough; and Dr. Bailey, lecture fees from Boston Scientific, Medtronic, and Abbott Vascular and research support from St. Jude Medical.
No other potential conflict of interest relevant to this letter was reported.
3 References1
Boden WE ,Taggart DP . Diabetes with coronary disease -- a moving target amid evolving therapies? N Engl J Med 2009;360:2570-2572
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Kapur A ,Malik IS ,Bagger JP , et al. The Coronary Artery Revascularisation in Diabetes (CARDia) trial: background, aims, and design. Am Heart J 2005;149:13-19
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Farkouh ME ,Dangas G ,Leon MB , et al. Design of the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) Trial. Am Heart J 2008;155:215-223
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To the Editor:
We would like to point out an aspect of the trial design that may have influenced the results of the BARI 2D study. In the group of patients who underwent CABG for revascularization, the authors defined perioperative myocardial infarction as an increase in the upper limit of the normal range for creatine kinase MB of 10 times.
Although the definition of myocardial infarction after CABG is a controversial topic, data from randomized trials have shown that an elevation of the level of creatine kinase MB that is five times higher than the reference range is a strong predictor of adverse events.1 This finding is highlighted in the current definition of post-CABG myocardial infarction proposed by the Joint European Society of Cardiology–American College of Cardiology Federation–American Heart Association–World Health Federation Task Force, which considers creatine kinase MB values to be abnormal if they are five times higher than the 99th percentile of the normal range.2
If the authors had used the current definition, a higher incidence of periprocedural myocardial infarction in the group of patients who underwent CABG would probably have resulted. Would the advantage of CABG over medical treatment in this subgroup of patients be smaller than the advantage proposed by the authors, or would it be nonexistent?
2 ReferencesEduardo G. Bertoldi, M.D.
Letícia S. Weinert, M.D.
Carisi A. Polanczyk, M.D., Sc.D.
Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
bertoldi@ymail.com 1
Costa MA ,Carere RG ,Lichtenstein SV , et al. Incidence, predictors, and significance of abnormal cardiac enzyme rise in patients treated with bypass surgery in the Arterial Revascularization Therapies Study (ARTS). Circulation 2001;104:2689-2693
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Thygesen K ,Alpert JS ,White HD , et al. Universal definition of myocardial infarction. Circulation 2007;116:2634-2653
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To the Editor:
In a “study . . . designed to reflect how physicians might confront treatment decisions in practice,” the BARI 2D investigators compared an insulin-sensitization strategy with an insulin-provision strategy in patients with type 2 diabetes and coronary artery disease. The patients assigned to the insulin-sensitization strategy mainly received metformin and rosiglitazone, whereas the patients assigned to the insulin-provision strategy mainly received sulfonylurea and insulin. On the basis of intermediate outcomes, the authors postulate, “These data may suggest that insulin sensitization is preferable for patients with type 2 diabetes and coronary disease.”
Metformin is the mainstay of treatment in type 2 diabetes, and metformin treatment should be maintained throughout the course of the disease.1 In one study, a 40% reduction in macrovascular disease was shown when metformin was added to insulin treatment.2 Although the BARI 2D study can be understood as a comparison of an insulin-sensitization strategy with an insulin-provision strategy, it is unfortunate that the standard of intensive treatment of type 2 diabetes (i.e., the combination of insulin and metformin) was not studied.
2 ReferencesJ. Hans DeVries, M.D., Ph.D.
Academic Medical Center, Amsterdam, the Netherlands
j.h. devries@amc. uva. nl 1
Nathan DM ,Buse JB ,Davidson MB , et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009;52:17-30
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Kooy A ,de Jager J ,Lehert P , et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009;169:616-625
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Author/Editor Response
We disagree with Pfisterer and Zellweger that the BARI 2D results are difficult to translate into practice. The BARI 2D trial emulates clinical practice in the treatment of patients with mild symptoms or no symptoms and documented ischemia who are undergoing clinically indicated angiography and for whom the revascularization strategy is based on coronary anatomy. We stress that patients with severe angina were not included in the study; thus, conclusions for such patients cannot be drawn from BARI 2D. Although several major clinical trials have compared invasive approaches with conservative approaches for ischemic heart disease,1-3 BARI 2D is unique because it focused on patients with diabetes. Only 19% of the patients who were randomly assigned to medical therapy underwent revascularization during the first year, and another 23% underwent revascularization between years 1 and 5; this is consistent with the natural progression of coronary disease in patients with diabetes.4 Our trial demonstrates that it is possible to limit mortality and major cardiovascular morbidity with the use of intensive medical therapy and the judicious use of delayed revascularization in patients with type 2 diabetes who do not require immediate intervention for symptom control.
We concur with Garratt and Bailey that the BARI 2D results should not be used to compare CABG with PCI. No advantage of prompt revascularization over medical therapy was seen for all-cause mortality in the PCI or CABG stratum, but the marked reduction in myocardial infarctions in the CABG stratum is of interest.
With regard to the question of Bertoldi et al.: myocardial infarctions were classified according to a carefully prespecified protocol. Biomarker release data were not used to classify myocardial infarction after the index revascularization procedure, but they were used, when available, to define myocardial infarction after follow-up revascularization procedures. The benefit for the composite outcome (death, myocardial infarction, or stroke) seen with CABG was statistically significant, regardless of whether or not procedure-related myocardial infarctions were included in the analysis. Periprocedural myocardial infarctions have been shown to be associated with increased long-term mortality rates after revascularization.5 However, among patients in the CABG stratum, the 5-year mortality rate was slightly lower with a strategy of prompt revascularization as compared with medical therapy, and the rate of late myocardial infarction was significantly lower.
We agree with DeVries that metformin is a mainstay of treatment for type 2 diabetes. The combination of insulin plus metformin was deliberately not studied because it would have confounded testing of the glycemic treatment hypothesis of BARI 2D. Our intermediate outcome results suggest that a strategy of reducing insulin resistance by adding a thiazolidinedione to metformin would be better than a strategy that relied primarily on insulin provision.
5 ReferencesMaria Mori Brooks, Ph.D.
University of Pittsburgh, Pittsburgh, PA
mbrooks@pitt.edu Bernard R. Chaitman, M.D.
Saint Louis University, St. Louis, MOMark E. Molitch, M.D.
Northwestern University Feinberg School of Medicine, Chicago, ILfor the BARI 2D Study Group
1
Boden WE ,O'Rourke RA ,Teo KK , et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-1516
Full Text | Web of Science | Medline2
Pepine CJ ,Bourassa MG ,Chaitman BR , et al. Factors influencing clinical outcomes after revascularization in the Asymptomatic Cardiac Ischemia Pilot (ACIP). J Card Surg 1999;14:1-8
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RITA-2 Trial Participants
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Alderman E ,Corley SD ,Fisher LD , et al. Five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study (CASS). J Am Coll Cardiol 1993;22:1141-1154
CrossRef | Web of Science | Medline5
Gavard JA ,Chaitman BR ,Sakai S , et al. Prognostic significance of elevated creatine kinase MB after coronary bypass surgery and after an acute coronary syndrome: results from the GUARDIAN trial. J Thorac Cardiovasc Surg 2003;126:807-813
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Author/Editor Response
Garratt and Bailey suggest that our statement that CABG surgery is the preferred approach to revascularization in patients with diabetes and stable coronary disease was not factual. We respectfully disagree. We clearly emphasized that among such patients who remained symptomatic despite intensive treatment or who had substantial ischemia or extensive coronary artery disease, revascularization with either PCI or CABG was reasonable and appropriate. We explicitly acknowledged that the BARI 2D design precluded any direct comparison between PCI and CABG with regard to clinical outcomes. However, we reasoned that the option of either PCI or CABG for revascularization, depending on the anatomical complexity of coronary disease, is a real-world strength of the trial. In addition, the significant reduction in the composite end point (death, myocardial infarction, or stroke) in patients with diabetes who underwent CABG would inevitably invite indirect comparisons between PCI and CABG among physicians faced with the clinical decision of which choice of revascularization is best suited for a given patient, particularly if the goal of revascularization is to reduce long-term clinical events (especially myocardial infarction). Our recommendation that CABG surgery is the preferred approach to revascularization in patients with diabetes and stable coronary disease is further supported by two other randomized trials1,2 and a recent meta-analysis.3
3 ReferencesWilliam E. Boden, M.D.
State University of New York at Buffalo, Buffalo, NYDavid P. Taggart, M.D., Ph.D.
Oxford University, Oxford, United Kingdom1
BARI Investigators
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Serruys PW ,Morice M-C ,Kappetein AP , et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961-972
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Hlatky MA ,Boothroyd DB ,Bravata DM , et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet 2009;373:1190-1197
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- Citing Articles (3)
Citing Articles
1
Michael J. Zellweger, Matthias E. Pfisterer. (2011) Therapeutic Strategies in Patients with Chronic Stable Coronary Artery Disease. Cardiovascular Therapeutics 29:6, e23-e30
CrossRef2
Yun Bai, Guozhu Yin, En Luo. (2011) Adiponectin may improve osseointegration of dental implants in T2DM patients. Medical Hypotheses 77:2, 192-194
CrossRef3
Rolf Dörr. (2010) Bypasschirurgie versus perkutane koronare Intervention bei Patienten mit Diabetes mellitus. Herz 35:3, 182-190
CrossRef
