CLINICAL RESEARCH: SURGERY VERSUS PCI WITH DES IN DIABETICS: EDITORIAL COMMENT
Percutaneous Coronary Intervention, Diabetes Mellitus, and Death*
Harold L. Dauerman, MD*
University of Vermont College of Medicine, Burlington, Vermont
* Reprint requests and correspondence: Dr. Harold L. Dauerman, Cardiac Unit, McClure 1, Fletcher Allen Health Care, University of Vermont, 111 Colchester Avenue, Burlington, Vermont 05401 (Email: harold.dauerman{at}vtmednet.org).
Key Words: diabetes mellitus • coronary artery bypass grafting • percutaneous coronary intervention
In this issue of the Journal, Banning et al. (1) present the important diabetes mellitus subgroup analysis of the SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) trial. The SYNTAX trial compared 1,800 patients with symptomatic left main and/or 3-vessel coronary artery disease (CAD) treated with drug-eluting stents (DES) versus coronary artery bypass graft surgery (CABG) (2). The overall results of the trial demonstrate 1-year inferiority of percutaneous coronary intervention (PCI) compared with CABG with respect to major adverse cardiac and cerebrovascular events (MACCE)—death, myocardial infarction (MI), stroke, or repeat revascularization (17.8% vs. 12.4%, p = 0.004). But the individual component end points are clinically relevant: mortality and MI rates were similar with either approach, stroke was 3.7-fold higher with CABG, and repeat revascularization was 2.3-fold higher with PCI. The pre-specified subgroup analysis of the 452 patients with diabetes demonstrates similar results as the overall trial: mortality and MI rates are similar at 1 year; stroke rates, though, are no longer statistically higher in the CABG group, but repeat revascularization remains threefold higher with PCI as compared with CABG. On the basis of the SYNTAX trial findings, have DES removed the "death penalty" associated with diabetes and multivessel PCI (3,4)?
 |
Diabetes and Death: An Accidental Finding
|
|---|
The BARI (Bypass Angioplasty Revascularization Investigation) trial was initiated by the National Heart, Lung, and Blood Institute in 1987 and firmly established diabetes as an important clinical risk factor among patients referred to cardiac catheterization laboratories (3,5). The BARI trial randomized approximately the same number of patients as SYNTAX to PCI versus CABG; the similarities between BARI and SYNTAX stop there (Table 1). The BARI study was a trial of balloon angioplasty, the SYNTAX study was a trial of DES. The SYNTAX study looked for left main disease, the BARI study excluded it. The BARI trial did not include periprocedural MI or 1 -year repeat revascularization in their primary or secondary end points, whereas SYNTAX used a broad and complex primary end point of MACCE. Given the contrasting nature of these trials, why look back and compare?
We look back to BARI and forward to BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) as these trials sandwich SYNTAX in a context that might simply be summarized as "PCI is bad for patients with diabetes and multivessel CAD." This is a major issue for clinicians: current registries estimate that approximately one-third of patients undergoing PCI have diabetes (6). There is a rationale for this definitive interpretation: the BARI diabetic subgroup showed a 15% lesser survival with PCI as compared with CABG at 5-year follow-up (3). And the BARI 2D trial failed to show a benefit of PCI as compared with intensive medical therapy among 1,605 stable, elective diabetic patients in the PCI stratum (7). Furthermore, the SYNTAX trial is a "negative trial" that failed to show noninferiority of MACCE for PCI as compared with CABG (2). Thus, all SYNTAX subgroup analyses may come with a disclaimer that negates their clinical impact.
The SYNTAX diabetes subgroup (n = 452) is 25% larger than the BARI diabetes subgroup (n = 365), and thus provides a significant amount of new and potentially important data. Before we assume that this pre-specified subgroup analysis is unable to influence clinical behavior, it is worthwhile to recall how the BARI trial influenced the culture of diabetes and revascularization: it was an accident mediated by an astute Data Safety and Monitoring Board after completion of trial enrollment from 1988 to 1991. As per the Methods section of the original BARI manuscript, "In 1992, the Safety and Data Monitoring Board requested an analysis of diabetic patients on the basis of published reports of adverse outcomes of PTCA after thrombolytic therapy in a subgroup of patients" (5,8). The startling relationship between diabetes, balloon angioplasty, and death discovered from this non–pre-specified subgroup analysis was not confirmed in the BARI registry, where clinicians were able to choose lower risk diabetic patients for PCI without conferring the death penalty (9). Nevertheless, the BARI trial subgroup analysis had a significant impact: the National Heart, Lung, and Blood Institute utilized this subgroup analysis to issue a Clinical Alert recommending CABG over angioplasty for diabetic patients (10).
Given that the diabetes mandate arose from a not pre-specified subgroup analysis, the BARI study authors appropriately caution the clinical implications of this finding with "appropriate concern about the potential of a spurious finding" (11). Despite the reliance on an ad hoc subgroup analysis, the Clinical Alert seems in hindsight to be appropriate, and balloon angioplasty for multivessel disease in diabetic patients seems like a very bad idea indeed. The 7- and 10-year follow-up of the BARI trial diabetic patient shows a persistent and growing benefit for survival with CABG as opposed to balloon angioplasty for patients with diabetes (11,12). More recently, a meta-analysis of 10 randomized trials of PCI (balloon angioplasty or bare metal stents) versus CABG for patients with multivessel CAD again suggests an interaction between death and revascularization strategy only for patients with treated diabetes (4). Thus, the diabetes subgroup analysis in the BARI trial was like the proverbial apple falling on Newton's head: it identified an entirely new way to look at an important issue—in this case, risk stratification for revascularization approaches based upon clinical (and not anatomic) criteria.
|
Diabetes and PCI: SYNTAX in Context
|
|---|
As with the BARI study, we should not ignore the clinical implications of the important subgroup analysis of diabetic patients despite the overall negative results of the SYNTAX trial. The SYNTAX investigators have discovered the following with respect to diabetes and revascularization: 1) at 1 year, there is no death penalty associated with multivessel PCI; 2) there are no differences in death/MI/stroke between CABG and PCI at 1 year; and 3) the use of DES fails to turn diabetic patients into nondiabetic patients—namely, the risk of repeat revascularization at 1 year remains substantially higher for diabetic patients as compared with nondiabetic patients, and threefold higher than for patients undergoing CABG. These findings are consistent with pathophysiologic differences between the responses to stent implantation of patients with and without diabetes (13).
The results of the SYNTAX subgroup analysis should also be seen in context: the 3-year results of the ARTS II (Arterial Revascularization Therapies Study-Part II) registry are concordant with SYNTAX and suggest similar long-term safety and mortality of DES-based PCI as compared with CABG for diabetic patients. Also similarly, repeat revascularization rates was higher with PCI for diabetic patients as compared with nondiabetic patients despite the use of DES (14).
What should a clinician do tomorrow when faced with a diabetic patient and multivessel CAD in the catheterization laboratory? The BARI 2D study helps us understand what is the current standard of care. The BARI 2D trial randomly allocated patients to intensive medical therapy versus revascularization, but replicated the BARI Registry with respect to revascularization: investigators could choose between PCI or CABG for patients with diabetes. Surprisingly, the majority of diabetic patients with multivessel CAD in the BARI 2D trial (56%) underwent PCI, not CABG (15). Furthermore, consistent with findings from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) registry, the preference for PCI grew after the approval of DES (16). Importantly, investigators in both the BARI 2D trial and the BARI Registry made revascularization choices on the basis of severity and extent of disease (i.e., proximal left anterior descending artery lesions, chronic total occlusions, triple-vessel disease) (15,17). Furthermore, patients did not necessarily present equivalent revascularization options: among patients assigned to PCI in the BARI 2D study, only 49% were deemed equally suitable for CABG; and among patients selected for CABG, only 11% were deemed suitable for PCI (15).
Thus, clinicians are already performing multivessel PCI in diabetic patients, many of whom investigators believe could not be served at all with CABG because of a variety of comorbidities (risk of stroke) or anatomic challenges (diffuse distal vessel disease, poor conduits). The SYNTAX study diabetes analysis does not tell those clinicians to stop doing PCI in diabetic patients. The SYNTAX study instead presents PCI as a viable general option with the following caveats: 1) multivessel PCI for diabetic patients performed without DES is likely associated with increased death and should not be done unless there is no reasonable surgical option (3,4); 2) diabetic patients undergoing PCI with DES remain at higher risk for repeat revascularization with PCI versus CABG. The influence of both culprit and nonculprit lesion progression in all diabetic patients should be considered (18,19); and 3) we cannot wait for the 5-year follow-up of the SYNTAX diabetes study to act clinically. It is possible that a death penalty is not seen at 1 year but will appear at longer follow-up periods. Ongoing studies, such as the FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) trial (20), can be expected to help further shape our choice of treatment strategies.
Finally, the SYNTAX study was a trial of complex, high-risk PCI performed by skilled investigators at high-volume institutions: can the findings be replicated in community practice? Although the SYNTAX trial no longer confirms the mortality risk associated with PCI for diabetic patients, the BARI study's accidental finding taught us an important lesson: PCI for patients with multivessel CAD and diabetes, like left main or bifurcation PCI, remains a higher risk procedure. We have no reason to believe that community clinicians cannot translate the results of the SYNTAX trial into a practice pattern that judiciously chooses diabetic patients for either CABG or DES-based PCI: both the old (BARI) and the new (EVENT [Evaluation of Drug-Eluting Stents and Ischemic Events]) registries have demonstrated that multivessel PCI for diabetes is feasible and safe outside the confines of a randomized clinical trial (6,9). Thus, reversal of the BARI trial mortality signal moves the diabetic revascularization choice away from the black-or-white, life-or-death decision the BARI trial once described; instead, we can move diabetes, CABG, and PCI back into the typical gray areas of clinical decision making that characterize routine practice.
|
Footnotes
|
|---|
Dr. Dauerman is a consultant to and/or has research grants from Abbott Vascular, Medtronic, The Medicines Company, St. Jude Medical, and Bristol-Myers Squibb.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
|
References
|
|---|
1. Banning AP, Westaby S, Morice M-C, et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting stents J Am Coll Cardiol 2010;55:1067-1075.[Abstract/Free Full Text]2. Serruys PW, Morice MC, 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.[CrossRef][Medline] 3. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI) Circulation 1997;96:1761-1769.[Abstract/Free Full Text] 4. 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.[CrossRef][Web of Science][Medline] 5. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease N Engl J Med 1996;335:217-225.[CrossRef][Web of Science][Medline] 6. Novack V, Tsyvine D, Cohen DJ, et al. Multivessel drug-eluting stenting and impact of diabetes mellitus—a report from the EVENT registry Catheter Cardiovasc Interv 2009;73:874-880.[CrossRef][Web of Science][Medline] 7. Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease N Engl J Med 2009;360:2503-2515.[CrossRef][Medline] 8. Mueller HS, Cohen LS, Braunwald E, et al. Predictors of early morbidity and mortality after thrombolytic therapy of acute myocardial infarction. Analyses of patient subgroups in the Thrombolysis In Myocardial Infarction (TIMI) trial, phase II. Circulation 1992;85:1254-1264.[Abstract/Free Full Text] 9. Feit F, Brooks MM, Sopko G, et al. Long-term clinical outcome in the Bypass Angioplasty Revascularization Investigation Registry: comparison with the randomized trial. BARI Investigators. Circulation 2000;101:2795-2802.[Abstract/Free Full Text] 10. U.S. National Library of Medicine Clinical Alert: Bypass Over Angioplasty for Patients With Diabetes, National Heart, Lung, and Blood Institute (NHLBI), September 21, 1995 http://www.nlm.nih.gov/databases/alerts/bypass_diabetes.html 2000Accessed September 2, 2009. 11. The BARI Investigators Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status J Am Coll Cardiol 2000;35:1122-1129.[Abstract/Free Full Text] 12. The BARI Investigators The final 10-year follow-up results from the BARI randomized trial J Am Coll Cardiol 2007;49:1600-1606.[Abstract/Free Full Text] 13. Aggarwal A, Schneider DJ, Sobel BE, Dauerman HL. Comparison of inflammatory markers in patients with diabetes mellitus versus those without before and after coronary arterial stenting Am J Cardiol 2003;92:924-929.[CrossRef][Web of Science][Medline] 14. Daemen J, Kuck KH, Macaya C, et al. Multivessel coronary revascularization in patients with and without diabetes mellitus: 3-year follow-up of the ARTS-II (Arterial Revascularization Therapies Study-Part II) trial J Am Coll Cardiol 2008;52:1957-1967.[Abstract/Free Full Text] 15. Kim LJ, King III SB, Kent K, et al. Factors related to the selection of surgical versus percutaneous revascularization in diabetic patients with multivessel coronary artery disease in the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial J Am Coll Cardiol Intv 2009;2:384-392.[Abstract/Free Full Text] 16. Gogo Jr. PB, Dauerman HL, Mulgund J, et al. Changes in patterns of coronary revascularization strategies for patients with acute coronary syndromes (from the CRUSADE Quality Improvement Initiative) Am J Cardiol 2007;99:1222-1226.[CrossRef][Web of Science][Medline] 17. Detre KM, Guo P, Holubkov R, et al. Coronary revascularization in diabetic patients: a comparison of the randomized and observational components of the Bypass Angioplasty Revascularization Investigation (BARI) Circulation 1999;99:633-640.[Abstract/Free Full Text] 18. Lee TT, Feinberg L, Baim DS, et al. Effect of diabetes mellitus on five-year clinical outcomes after single-vessel coronary stenting (a pooled analysis of coronary stent clinical trials) Am J Cardiol 2006;98:718-721.[CrossRef][Medline] 19. Chacko R, Mulhearn M, Novack V, et al. Impact of target lesion and nontarget lesion cardiac events on 5-year clinical outcomes after sirolimus-eluting or bare-metal stenting J Am Coll Cardiol Intv 2009;2:498-503.[Abstract/Free Full Text] 20. 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.[CrossRef][Web of Science][Medline]
Related Articles
-
Inside This Issue
J. Am. Coll. Cardiol. 2010 55: A27.
[Full Text]
[PDF]
-
Diabetic and Nondiabetic Patients With Left Main and/or 3-Vessel Coronary Artery Disease: Comparison of Outcomes With Cardiac Surgery and Paclitaxel-Eluting Stents
- Adrian P. Banning, Stephen Westaby, Marie-Claude Morice, A. Pieter Kappetein, Friedrich W. Mohr, Sergio Berti, Mattia Glauber, Mirle A. Kellett, Robert S. Kramer, Katrin Leadley, Keith D. Dawkins, and Patrick W. Serruys
J. Am. Coll. Cardiol. 2010 55: 1067-1075.
[Abstract]
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
D. Capodanno, C. Tamburino, G. M. Sangiorgi, E. Romagnoli, A. Colombo, F. Burzotta, G. L. Gasparini, L. Bolognese, L. Paloscia, P. Rubino, et al.
Impact of Drug-Eluting Stents and Diabetes Mellitus in Patients With Coronary Bifurcation Lesions: A Survey From the Italian Society of Invasive Cardiology
Circ Cardiovasc Interv,
February 1, 2011;
4(1):
72 - 79.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, J. J. Bax, O. Ben-Yehuda, G. K. Feld, B. H. Greenberg, J. Hall, M. Hlatky, W. Y. W. Lew, J. A. C. Lima, A. S. Maisel, et al.
Highlights of the Year in JACC 2010
J. Am. Coll. Cardiol.,
January 25, 2011;
57(4):
480 - 514.
[Full Text]
[PDF]
|
|
|
|
Top
Diabetes and Death: An...
Diabetes and PCI: SYNTAX...