CLINICAL RESEARCH
The Prognostic Importance of Nonsignificant Left Main Coronary Artery Disease in Patients Undergoing Percutaneous Coronary Intervention
Gabor Gyenes, MD, PhD*,*,
Fiona M. Shrive, BSc ,
Michelle M. Graham, MD, FRCP(C)*,
William A. Ghali, MD, FRCP(C),
Merrill L. Knudtson, MD, FCRP(C) the APPROACH Investigators
* University of Alberta, Edmonton, Alberta, Canada
University of Calgary, Calgary, Alberta, Canada
Manuscript received December 31, 2005;
revised manuscript received February 16, 2006,
accepted February 21, 2006.
* Reprint requests and correspondence: Dr. Gabor Gyenes, University of Alberta Hospital, 2C2 Walter Mackenzie Health Sciences Centre, 8440-112 Street, Edmonton, AB, Canada T6G 2B7 (Email: ggyenes{at}cha.ab.ca).
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Abstract
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OBJECTIVES: The purpose of this research was to study the association between nonsignificant (<50%) left main coronary artery disease (LMCAD) and short- and long-term survival in patients undergoing percutaneous coronary intervention (PCI).
BACKGROUND: The prognostic importance of nonsignificant LMCAD is unknown; however, the co-existence of nonsignificant LMCAD may influence revascularization decisions.
METHODS: We analyzed mortality and repeat catheterization rates of 11,855 patients in a prospective cardiac registry database who underwent single-vessel or multivessel PCI from January 1996 through December 2001. Of this cohort, 11.7% (n = 1,385) had nonsignificant (<50%) LMCAD. Outcomes were compared with those without LMCAD. A secondary analysis was performed on a larger cohort of 34,586 patients undergoing cardiac catheterization, irrespective of mode of revascularization therapy.
RESULTS: Patients with nonsignificant LMCAD had more co-morbidities, and a significantly higher crude mortality rate at 1 year compared with those without LMCAD (4.4% vs. 3.4%; p = 0.05). The 7-year crude mortality hazard ratio (HR) of PCI patients with <50% LMCAD versus those with no LMCAD was 1.18 (95% confidence interval [CI] 0.94 to 1.46). After risk adjustment for differences in baseline clinical profile, however, the HR decreased to 0.98 (95% CI 0.79 to 1.23). Repeat catheterization rates at 1 year did not differ between groups. The secondary analysis in all patients with nonsignificant LMCAD showed an adjusted HR of 1.03 (95% CI 0.94 to 1.14).
CONCLUSIONS: Patients undergoing single-vessel or multivessel PCI who have <50% LMCAD have a nonsignificantly increased 18% relative risk for mortality compared with those without detectable LMCAD that appears to be related to these patients' higher incidence of co-morbidities rather than the left main stenosis itself.
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Abbreviations and Acronyms
| | APPROACH = Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease | | CABG = coronary artery bypass grafting | | CI = confidence interval | | HR = hazard ratio | | IVUS = intravascular ultrasound | | LMCAD = left main coronary artery disease | | PCI = percutaneous coronary intervention |
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It is widely accepted that significant ( 50%) left main coronary artery disease (LMCAD) is associated with an increased cardiac mortality. Previous studies have found coronary artery bypass grafting (CABG) to provide superior long-term outcomes than medical management in these patients (1–4). Although repeatedly challenged by interventional cardiologists, percutaneous coronary intervention (PCI) has traditionally been regarded as a relatively high-risk revascularization option for significant LMCAD. Therefore, for the majority of patients, CABG is currently considered the revascularization strategy of choice.
The prognostic importance of nonsignificant (<50%) LMCAD, however, is less clear. Despite the lack of supportive scientific evidence, the co-existence of nonsignificant LMCAD with disease of other coronary arteries may influence decisions for revascularization options. Some physicians feel more comfortable recommending surgery to these patients rather than PCI because of perceived risks, presumably related to plaque rupture in the diseased left main coronary artery, a possible higher risk of proximal disease progression, or an increased risk of guide catheter-induced left main complications with PCI.
Recognizing these therapeutic considerations and the relative paucity of data on nonsignificant LMCAD, we conducted a study of patients undergoing PCI to determine the association between nonsignificant LMCAD and both short- and long-term survival. This outcome analysis is complemented by a secondary analysis in which we assessed outcomes associated with nonsignificant LMCAD in a broader collective of patients undergoing cardiac catheterization, regardless of revascularization treatment received.
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Methods
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The APPROACH (Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease) database was utilized to identify a suitable patient cohort; APPROACH is a clinical data collection initiative and prospective outcome cohort database with longitudinal follow-up that has captured all patients undergoing catheterization and revascularization in Alberta, Canada, since 1995. It contains detailed clinical information including cardiac risks, cardiac history, co-morbidities, and previous revascularization; APPROACH is linked semiannually to data from the Alberta Bureau of Vital Statistics to generate survival data on patients in the cohort.
Patient selection.
Over 40,000 residents of Alberta, Canada, had a diagnostic coronary angiogram from January 1996 through December 2001. Patients with previous CABG were excluded. Of the remaining 37,188 patients, we excluded 2,602 who had significant (>50%) LMCAD. Thereafter, the remaining 34,586 were divided into 2 subgroups: 30,418 had no documented LMCAD and 4,168 (12.1%) had nonsignificant LMCAD. In our primary analysis, we excluded all patients from both groups who were subsequently referred for surgery, and those who were managed medically after the index catheterization. This yielded a study cohort of 11,855 patients undergoing single-vessel or multivessel PCI, within which 1,385 individuals (11.7%) had documented nonsignificant (<50%) LMCAD. Comparisons were made between these 2 subgroups. In a secondary analysis done to avoid the potential selection bias associated with focusing only on PCI patients, we included all of the 34,586 patients undergoing cardiac catheterization and adjusted the outcomes in the LMCAD and no LMCAD groups (see analysis section in the following text) for both clinical variables and treatment.
Statistical methods.
We used chi-square tests to compare the baseline clinical characteristics between subgroups. Crude repeat catheterization rates 1 year after PCI are reported to see whether differences in in-stent restenosis rates influenced survival. Both 30-day and 1-year mortality as well as long-term (7-year) survival were assessed by producing crude Kaplan-Meier curves. We then used a Cox proportional hazards analysis (after confirming the appropriateness of the proportional hazards assumption) to determine risk-adjusted survival after PCI, controlling for age, gender, left ventricular function, multivessel disease, and all co-morbidities contained in the APPROACH database as shown in Table 1. Risk-adjusted survival curves were generated using the corrected group prognosis method (5). These same analyses were replicated in our secondary analysis of all patients undergoing cardiac catheterization. All analyses were conducted using SAS version 8.1 (SAS Institute, Cary, North Carolina).
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Results
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Baseline characteristics are shown in Table 1. The PCI patients with nonsignificant LMCAD were more often men. They also had more co-morbidities such as diabetes, renal disease, congestive heart failure, a prior history of PCI, and previous smoking. They were, however, less likely to be current smokers at the time of the index catheterization.
Outcomes at 30 days and 1 year are shown in Table 2. There were similar re-catheterization rates in the 2 groups (p = 0.58) suggesting that any potential differences in outcomes were not due to different in-stent restenosis rates between the 2 groups. There was no difference in mortality at 30 days, but we observed an increased crude mortality at 1 year in patients with nonsignificant LMCAD.
Crude and adjusted survival curves are depicted in Figures 1 and 2, respectively. We observed an 18% relative excess mortality at 7 years in patients with nonsignificant LMCAD (crude hazard ratio [HR] 1.18 [95% confidence interval (CI) 0.94 to 1.46]) that was not statistically significant. After risk-adjustment for all the variables contained in the APPROACH database, however, the curves became almost superimposed, and the relative risk dropped to 0.98 (95% CI 0.79 to 1.23).
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Figure 1 Seven-year crude survival of percutaneous coronary intervention patients with no left main coronary artery disease (LMCAD) versus percutaneous coronary intervention patients with "nonsignificant" (i.e., <50%) LMCAD. Thin line = no LMCAD; thick line = LMCAD <50%.
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Figure 2 Seven-year risk-adjusted survival of percutaneous coronary intervention patients with no left main coronary artery (LMCAD) disease versus percutaneous coronary intervention patients with <50% LMCAD. Solid line = LMCAD <50%; dashed line = no LMCAD.
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Our secondary analysis of all patients undergoing cardiac catheterization revealed similar trends. The crude mortality rates for the expanded cohort of patients with nonsignificant LMCAD, regardless of treatment received (n = 34,586), are shown in Table 3. Patients with nonsignificant LMCAD had a crude mortality HR of 1.38 (95% CI 1.26 to 1.51) compared with those without LMCAD. When adjusted for clinical variables, the HR dropped to 1.03 (95% CI 0.94 to 1.14). After adjustment for both clinical variables and subsequent treatment received (i.e., PCI, CABG, or medical therapy alone), the adjusted HR was 1.04 (95% CI 0.95 to 1.14).
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Discussion
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Our findings reveal an 18% excess mortality over 7 years in PCI patients with nonsignificant LMCAD compared with patients with no documented LMCAD. Risk-adjustment resulted in a hazard ratio of 0.98 indicating that it may not be the nonsignificant LMCAD per se that confers the higher risk, but rather the associated co-morbidities. This statement is also supported by the fact that our patients with documented nonsignificant LMCAD were generally sicker (i.e., they had more co-morbidities than patients without LMCAD). The secondary analysis of all patients undergoing cardiac catheterization showed similar results for the full cohort, suggesting that a selection bias associated with undergoing PCI did not influence the results of our primary analysis.
There is a paucity of data on so-called "nonsignificant" LMCAD. Our study is the largest published series of patients with nonsignificant LMCAD that we could find in the literature. However, there are some smaller studies available for significant but not critical LMCAD. Conley et al. (6) identified a relatively low-risk subgroup of 53 patients with significant (50% to 70%) left main stenosis and 3-vessel coronary artery disease who had a similar 3-year survival to the 479 patients with 3-vessel disease and normal left main coronary artery. Using nuclear stress tests, Amanullah et al. (7) were also able to identify a subgroup of patients with significant left main disease who have a low subsequent cardiovascular event rate (7).
More recent studies have used intravascular ultrasound (IVUS) to assess subclinical left main disease. This imaging modality may be able to detect atherosclerotic plaques that may remain invisible on an angiogram. The inherent limitation of the visual assessment of coronary angiograms also constitutes one of the potential limitations of our study. As the left main coronary artery is generally short and its diameter varies considerably between 5 to 10 mm (8), it may be especially difficult to properly assess the presence or absence of a nonobstructive plaque. In a study by Hermiller et al. (9), 24 of 27 patients with angiographically normal left main coronary artery had a detectable plaque by IVUS. One study published data on 107 patients undergoing PCI with angiographically normal or mild left main disease who had simultaneous IVUS imaging (10). Whereas the severity of left main coronary artery area stenosis on qualitative coronary angiography was 18.2 ± 9.8%, it was 30.2 ± 14.7% on IVUS. During a median follow-up of 29 months (range 8 to 52 months), there were few events documented, but in a multivariate analysis diabetes mellitus and the minimum luminal area on IVUS appeared to correlate with a worse prognosis. Nevertheless, the authors allowed for the possibility that more LMCAD may simply reflect more widespread underlying vascular pathology. In an even smaller but very similar study, 30 patients underwent both single-vessel coronary interventions and an IVUS of the left main coronary artery (11). Twenty-one patients appeared to have normal left main coronary artery by angiography, but all showed some plaque on IVUS. Eight of the 9 patients who had a cardiovascular event during the 38-month (range 27 to 47 months) follow-up had a left main coronary artery area stenosis 20%. Johnston et al. (12) proposed that centers should more frequently perform IVUS in concert with the angiographic assessment of the left main so these measurements could then be correlated to long-term clinical outcomes to better establish the natural history of LMCAD and the threshold for intervention.
In our study, only 11.7% of patients had documented nonsignificant LMCAD. The findings of the above-mentioned IVUS studies, however, would imply that we almost certainly missed some cases with left main coronary artery stenosis. Thus, the possibility that we compared a group of patients with angiographically silent but potentially existing nonsignificant LMCAD with patients with angiographically visible nonsignificant LMCAD has to be considered. However, the observed crude mortality of 12% to 14% over 7 years does not suggest that 2 high-risk groups were compared with each other. It appears that the more severe left main plaque burden detected by IVUS reflects more severe underlying vascular pathology that is related to a higher incidence of risk factors and co-morbidities. This is supported by our finding that more LMCAD may lead to an increased mortality through co-morbidities rather than the LMCAD itself.
Our findings are important because they suggest that the mode of revascularization or the decision to proceed with revascularization should not necessarily be influenced by the presence of "nonsignificant" LMCAD in and of itself. Despite the evidence that patients with 50% left main coronary artery stenosis have an increased cardiovascular mortality, our findings suggest that adverse prognosis associated with LMCAD is less of a concern when the extent of LMCAD is modest and causing less than 50% stenosis.
To summarize, our study reveals an increased relative risk of mortality in patients with nonsignificant (<50%) LMCAD that appears to be related to these patients' higher prevalence of co-morbidities rather than the left main coronary artery stenosis itself. These findings suggest that the presence of nonsignificant LMCAD should not be considered as a major factor in decisions regarding the need for, and the mode of, revascularization.
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Appendix
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The APPROACH Clinical Steering Committee: Edmonton—S. Archer, M.M. Graham, W. Hui, A. Koshal, R.T. Tsuyuki (Chair), and C.M. Norris; Calgary—L.B. Mitchell, M.J. Curtis, W.A. Ghali, M.L. Knudtson, A. Maitland, M. Traboulsi, and P.D. Galbraith. Dr. Ghali is a Population Health Investigator of the Alberta Heritage Foundation for Medical Research (AHFMR), Edmonton, Alberta, and a Government of Canada Research Chair in Health Services Research. F.M. Shrive is supported by a Canada Graduate Scholarship from the Canadian Institute for Health Research and a full-time studentship from AHFMR.
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Acknowledgments
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The authors appreciate the assistance of the Calgary Health Region and the Capital Health Authority in supporting data entry by cardiac catheterization laboratory personnel.
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Footnotes
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APPROACH was funded in 1995 by the Weston Foundation, with ongoing support from Merck Frosst Canada Inc., Monsanto Canada Inc., Searle, Eli Lilly Canada Inc., Guidant Corporation, Boston Scientific Ltd., Hoffmann-La Roche Ltd., Johnson & Johnson Inc.-Cordis, and the Province-Wide Services Committee of Alberta Health and Wellness.
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References
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1. Coronary Artery Surgery Study (CASS) Principal Investigators and Associates CASS: a randomized trial of coronary bypass surgery Circulation 1983;68:939-950.[Abstract/Free Full Text]2. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina N Engl J Med 1984;311:1333-1339.[Abstract] 3. Varnauskas E, the European Coronary Surgery Study Group Twelve-year follow-up of survival in the randomized European Coronary Surgery study N Engl J Med 1988;319:332-337.[Abstract] 4. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration Lancet 1994;344:563-570.[CrossRef][Web of Science][Medline] 5. Ghali WA, Quan H, Brant R, et al. , for the APPROACH InvestigatorsComparison of 2 methods for calculating adjusted survival curves from proportional hazard models. JAMA 2001;286:1494-1497.[Abstract/Free Full Text] 6. Conley MJ, Ely RE, Kisslo J, Lee KL, McNeer F, Rosati RA. The prognostic spectrum of LM stenosis Circulation 1978;57:947.[Abstract/Free Full Text] 7. Amanullah AM, Heo J, Acio E, Narula J, Iskandrian AE. Predictors of outcome of medically treated patients with left main/three-vessel coronary artery disease by coronary angiography Am J Cardiol 1999;83:445-448.[Medline] 8. Conti CR, Selby JH, Christie LG, et al. Left main coronary artery stenosis: clinical spectrum, pathophysiology, and management Prog Cardiovasc Dis 1979;22:73-106.[CrossRef][Web of Science][Medline] 9. Hermiller JB, Buller CE, Tenaglia AN, et al. Unrecognized left main coronary artery disease in patients undergoing interventional procedures Am J Cardiol 1993;71:173-176.[CrossRef][Web of Science][Medline] 10. Ricciardi MJ, Meyers S, Choi K, Pang JL, Goodreau L, Davidson CJ. Angiographically silent left main disease detected by intravascular ultrasound: a marker for future adverse cardiac events Am Heart J 2003;146:507-512.[CrossRef][Web of Science][Medline] 11. Burns WB, Hermiller JB, Kisslo K, Culp S, Davidson CJ. Prognostic significance of left main coronary artery disease detected by intravascular ultrasound J Invasive Cardiol 1995;7:119-121.[Medline] 12. Johnston PW, Fort S, Cohen EA. Noncritical disease of the left main coronary artery: limitations of angiography and the role of intravascular ultrasound Can J Cardiol 1999;15:297-302.[Web of Science][Medline]
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Abstract
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