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Original Articles: Adult Cardiac

Decision-Making for Patients With Patent Left Internal Thoracic Artery Grafts to Left Anterior Descending

^a Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio
^b Department of Quantitative Health Sciences, Research Institute, Cleveland Clinic, Cleveland, Ohio

Accepted for publication February 12, 2009.

^_* Address correspondence to Dr Sabik, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Ave, Mail Stop J4-1, Cleveland, OH 44195 (Email: sabikj{at}ccf.org).

This paper was presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 
Background: It is unknown whether coronary reintervention confers a survival advantage when a previously placed left internal thoracic artery graft to the left anterior descending coronary artery (LAD) is patent. We compared survival after medical therapy, percutaneous intervention, and reoperative coronary artery bypass grafting in such patients who developed non-LAD territory jeopardy.

Methods: From 1971 to 2000, 4,640 patients with prior coronary artery bypass grafting that included left internal thoracic artery to LAD grafting were found on angiography during active follow-up to have a patent left internal thoracic artery to LAD graft, but at least 50% stenosis of non-LAD territories or grafts to them. Two survival analyses were performed: (1) intent-to-treat, which included patients undergoing reoperative coronary artery bypass grafting (n = 731) or percutaneous intervention (n = 994) within 6 weeks of angiography or medical management (n = 2,782), and (2) competing risk/crossover, in which patients were classified as medically managed until crossover to coronary artery bypass grafting or percutaneous intervention.

Results: In the intent-to-treat analysis, propensity-adjusted early (<1 year) survival was similar for all patients, but late survival was slightly better after percutaneous intervention than with medical management (p 0.05). In the competing risk/crossover analysis, adjusted survival was best for medically treated patients early; however, late survival was similar among all three groups.

Conclusions: Patients with patent left internal thoracic artery to LAD grafts who develop non-LAD territory jeopardy derive no survival benefit from reintervention, consistent with previous observations that for coronary reintervention to improve survival, the LAD territory must be jeopardized. Reintervention in patients with a patent left internal thoracic artery to LAD graft may be warranted to relieve symptoms, without expecting a survival benefit.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 
Although indications for coronary artery bypass grafting (CABG) are well described for patients without prior surgical revascularization, benefits of coronary revascularization are less well known for patients with prior CABG and patent bypass grafts. Ischemia in the distribution of the left anterior descending coronary artery (LAD) is necessary for CABG to improve survival compared with medical therapy [1]. Patients presenting with recurrent ischemia after prior CABG and a patent internal thoracic artery (ITA) to their LAD do not have anterior wall ischemia and therefore would not be expected to derive a survival benefit from revascularization. To test this hypothesis, we compared survival of patients with prior CABG, patent ITA-to-LAD graft, and non-LAD ischemia who were treated medically, with reoperative CABG, or with percutaneous intervention (PI).

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 
Patients
Using our Cardiovascular Information Registry, patients were identified and included in this study if they had (1) previous isolated CABG; (2) angiography at Cleveland Clinic from 1971 to 2000 demonstrating myocardial jeopardy in non-LAD territories, determined by native coronary artery stenosis of at least 50%, bypass graft stenosis of at least 50%, or both, and a patent, nonstenosed, left ITA graft to the LAD; (3) no intervening coronary reintervention between primary CABG and index angiography; and (4) no other cardiac disease requiring operation. During this period, 6,188 patients met these criteria. Of these, 1,538 had reoperative isolated CABG (except 1 patient who underwent laser transmyocardial revascularization), 1,470 PI, and 3,180 no documented reintervention as of last follow-up. Among patients with no documented reintervention, 1,632 (51%) were actively followed at Cleveland Clinic; the remaining 1,548 patients were not included in the study. Thus, a total of 4,640 patients had data available for analyses.

Data
Patient variables were obtained from the Cardiovascular Information Registry, and time of death after reintervention was determined using the Social Security Death Index [2, 3]. Use of these data for clinical research was approved by the Cleveland Clinic's Institutional Review Board, with patient consent waived.

Mean follow-up was 12 ± 7.5 years, with 55,303 patient-years of data available for analyses. Among survivors, follow-up ranged from 1 day to 35 years, with a median of 13 years (15th and 85th percentiles, 8.2 and 22 years).

Statistical Methods
Two types of analysis were performed: an intent-to-treat analysis (Coronary Artery Surgery Study method 2) and a competing risk/crossover analysis (Coronary Artery Surgery Study method 1) [4].

Intent-to-treat analysis
In this analysis, patients were stratified into one of three groups by whether they had (1) reoperative CABG, (2) PI, or (3) no reintervention within a specific time from index angiogram. To determine the appropriate length of time after angiography to identify the group into which a patient should be stratified, the cumulative distribution of time from index angiogram to reintervention was used (Fig 1). Based on this distribution, we chose 6 weeks as the cutoff point. Therefore, the medical intent-to-treat group included all patients not undergoing reintervention within 6 weeks of index angiogram; patients having reoperative CABG or PI within this 6-week period were included in their respective reintervention groups. Despite the observation that many patients in the medical arm of the study underwent reintervention after 6 weeks, in this analysis they remained in the medical group.

View larger version (10K): [in this window] [in a new window]   Fig 1. Cumulative distribution for time from angiography to first reintervention (either coronary artery bypass grafting [CABG] or percutaneous intervention [PI]).

Survival
Intent-to-treat analysis
Survival for each of the three treatment groups was estimated nonparametrically by the method of Kaplan and Meier and parametrically by multiphase hazard methodology [7]. (For additional details, see http://www.clevelandclinic.org/heartcenter/hazard.) Time zero was the time of reintervention for CABG and PI groups, and 6 weeks after the index angiogram for the medical group. Patients dying within 6 weeks with no reintervention were eliminated from this analysis.

To adjust for differences in preoperative risk profiles of patients and their original operations in the three groups, propensity scores were generated based on clinical data at the time of index angiogram [8, 9]. Multivariable polytomous logistic regression was performed to identify factors (Appendix Table 1) associated with each of the three management groups. Bootstrap aggregation [10] (bagging) using the median rule was used for variable selection, including linearizing transformations of continuous and ordinal variables. The probability value criterion for retention of variables was 0.05 (Appendix Table 2). Three propensity scores were calculated for each patient: the probability of being in the PI, reoperative CABG, or medical groups. These scores were then forced into survival models to adjust for preoperative patient differences [11].

Competing risk/crossover analysis
In the competing risk/crossover analysis, time zero for survival analysis for all patients was the date of index angiogram, and patients were censored as they crossed over to reintervention. Time zero for the reintervention patients was the date of PI or the date of reoperative CABG. For risk adjustment, multivariable analysis was performed using hazard multiphase methodology. Bootstrap aggregation using the median rule was used for variable selection (Appendix Table 1 and three treatment strategies), including appropriate transformations of continuous and ordinal variables. In addition, the interval from the index angiogram and age at reintervention were added to the analyses. Interactions among statistically significant variables were sought. The probability value criterion for retention of variables was 0.05.

	Results

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 
Survival
Intent-to-treat analysis
Unadjusted survival at 1, 5, 10, 15, and 20 years was 97%, 88%, 72%, 56%, and 42% for the medical group; 95%, 83%, 64%, 50%, and 36% for the PI group; and 94%, 85%, 66%, 47%, and 36% for the reoperative CABG group (Fig 2). A two-phase instantaneous risk of mortality (hazard) model was identified, consisting of an early hazard phase lasting about 1 year and an increasing late hazard phase. Unadjusted survival was better early and late in the medical group versus the reoperative CABG (p = 0.0002 for early hazard, p = 0.02 for late hazard) and PI (p = 0.0002 for early hazard, p = 0.0014 for late hazard) groups, but similar for the reoperative CABG and PI (p = 0.9 for early hazard, p = 0.5 for late hazard) groups.

View larger version (16K): [in this window] [in a new window]   Fig 2. Survival for reoperative coronary artery bypass grafting (CABG; red squares), percutaneous intervention (PI; blue triangles), and medically treated (Medical; green filled circles) groups in the intent-to-treat analysis. Symbols represent nonparametric estimates and 68% confidence limits at 1, 5, 10, 15, and 20 years, and numbers in parentheses are patients remaining at risk. Solid lines are parametric estimates enclosed within dashed 68% confidence limits.

Competing risk/crossover analysis
Although most reinterventions occurred shortly after index angiography, crossovers occurred at a fairly steady rate of 2% per year for PI, but increased to nearly 5% per year by 20 years for reoperative CABG (Fig 3). Unadjusted survival at 1, 5, 10, 15, and 20 years before reintervention (medical group) was 98%, 90%, 77%, 64%, and 44%, after PI was 95%, 83%, 64%, 50%, and 37%, and after reoperative CABG was 94%, 85%, 66%, 47%, and 37%, respectively (Fig 4). After risk adjustment, revascularization with PI and reoperative CABG resulted in higher early mortality, but neither reliably reduced late mortality (Table 5).

View larger version (14K): [in this window] [in a new window]   Fig 3. Hazard function for competing risk of reoperative coronary artery bypass grafting (CABG; red), percutaneous intervention (PI; blue), and death before either intervention (Medical; green). Solid lines are parametric estimates enclosed within dashed 68% confidence limits.

View larger version (16K): [in this window] [in a new window]   Fig 4. Survival after reoperative coronary artery bypass grafting (CABG; red squares), after percutaneous intervention (PI; blue triangles), and before reintervention (green filled circles) in the competing risk/crossover analysis.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

Background
Randomized trials comparing initial medical therapy with CABG demonstrated that LAD ischemia was necessary for CABG to prolong survival over medical therapy [1]. When ischemia was present in only the distribution of the right or circumflex coronary arteries, CABG was no better than medical therapy in improving survival. It would therefore be logical to assume that unless a patient with prior CABG has LAD ischemia, CABG or PI would be no more effective than medical therapy in prolonging survival. This is in line with our findings, as patients with a patent ITA-to-LAD graft do not have anterior wall ischemia.

Sergeant and colleagues [12] and Blackstone [13] found that when angina returned in patients with previous CABG and a patent ITA-to-LAD graft, survival was no different from that of similar post-CABG patients who had no return of ischemic symptoms. These observations suggest that, similar to patients without prior CABG, recurrent ischemia in non-LAD territories of the myocardium after surgical revascularization does not decrease survival. Therefore, it would be rational to assume that revascularizing non-LAD ischemic territories in patients with a patent ITA-to-LAD graft would not improve survival. Our observations support this assumption.

Limitations
In this study, we used two types of analyses to investigate whether reoperative CABG or PI is better at prolonging survival in patients with myocardial ischemia and a patent ITA-to-LAD graft. Both methods have strengths and weaknesses.

The intent-to-treat analysis most closely simulates a randomized trial. In this method, patients are grouped by initial treatment assignment made after review of the index angiogram. Any clinical event that occurs after the initial treatment decision does not bias group assignment. A weakness of this type of analysis, however, is that the medical arm of the study does not include only patients who received medical therapy alone; many patients initially assigned to the medical group underwent coronary reintervention after the initial assignment period. This may result in survival in the medical group appearing better than it actually would be if patients were limited to medical therapy alone.

The competing risk/crossover analysis, by contrast, gives the best estimate of the results of medical therapy because only patients who received medical therapy alone are included in the group. Similar to the intent-to-treat analysis, this method may introduce bias against PI and reoperative CABG. As patients' clinical situations deteriorate and medical therapy fails, they may undergo a revascularization procedure for relief of symptoms. These "sicker" patients are therefore removed from the medical group and added to either the reoperative CABG or PI group. This may in part explain the lack of improved late survival in the revascularization groups.

Despite the weaknesses of both methods, each is beneficial in demonstrating that medical therapy is an effective first-line therapy in symptomatic patients with a patent ITA-to-LAD graft, and that as patients' clinical situations change (ie, symptoms worsen), they may undergo either surgical or percutaneous revascularizations without compromising their survival. This is in agreement with recent findings that contemporary medical management of chronic stable angina is as effective as reintervention [14].

A minority of patients in this study had bilateral ITA grafting at their primary CABG. Those who were included in this study rarely had reoperative CABG (Table 2), but were primarily treated medically when ischemia recurred. Survival was similar in patients treated with bilateral and single ITA grafting in this population; however, this study lacks power to identify a statistically significant survival benefit of bilateral ITA grafting, which we have demonstrated previously [15–18].

Clinical Inferences
Initial medical therapy in symptomatic patients with non-LAD myocardial ischemia and patent ITA-to-LAD grafts is as effective in prolonging survival as reoperative CABG and PI. Coronary reintervention in these patients should be reserved for treatment of symptoms when medical therapy fails or is unacceptable to the patient. Choice of revascularization technique should take into account the expected effectiveness and risk of the two procedures. In addition, at primary CABG, an ITA should routinely be used to revascularize the LAD.

	Appendix Table 1

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 
Variables Used in Multivariable Analyses

Demographics Age (y), sex, height (cm), weight (kg), body surface area (m2), body mass index (kg/m2) a Preoperative status NYHA functional class (I–IV), Canadian angina class (1–4), emergency operation Cardiac comorbidity Left ventricular function, previous myocardial infarction, preoperative atrial fibrillation, family history of coronary artery disease, ventricular arrhythmia, complete heart block, history of endocarditis, history of heart failure Noncardiac comorbidity Treated diabetes, hypertension, previous stroke, history of smoking, peripheral arterial disease, chronic obstructive pulmonary disease, renal failure, blood urea nitrogen (mg/dL), creatinine (mg/dL), bilirubin (mg/dL), cholesterol (total, high-density lipoprotein, low-density lipoprotein [mg/dL]), triglycerides (mg/dL), hematocrit (%) Index angiogram Number of coronary systems with 50% stenosis; stenosis of LAD, LMT, RCA, LCx (native and grafts); jeopardized LCx system; jeopardized RCA system b Primary CABG Saphenous vein graft to LAD, LCx, RCA, diagonal; internal thoracic artery (free, in situ, left, right) graft to LCx, RCA, diagonal; number of distal anastomoses; place of surgery (Cleveland Clinic) Experience Date of angiogram, c interval from primary CABG to angiogram Additional variables for intent-to-treat analysis PI within 6 weeks of angiogram, CABG within 6 weeks of angiogram Additional variables for competing risk/crossover analysis Intervention group (medical, PI, CABG), interval from index angiogram to intervention, age at intervention (y) a (Body mass index/40), inverse transformation. b Jeopardized systems were defined as the minimum of (1) maximum stenosis in the native vessel and (2) maximum stenosis in the graft. c 1/(years from 1/1/1971 to date of angiogram), inverse transformation.

CABG = coronary artery bypass grafting; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; LMT = left main trunk; NYHA = New York Heart Association; PI = percutaneous intervention; RCA = right coronary artery.

	Appendix Table 2

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 
Propensity Model: Polytomous Logistic Regression Model for Intent-to-Treat Groups With Coronary Artery Bypass Grafting Group as the Reference Group

Factor Medical Percutaneous Intervention Overall Coefficient ± SEM p Value Coefficient ± SEM p Value p Value Demographics  Age –0.14 ± 0.047 0.003 –0.15 ± 0.05 0.004 0.007  Age a 2.2 ± 0.68 0.001 2.3 ± 0.72 0.002 0.002  Female –0.13 ± 0.14 0.3 –0.14 ± 0.15 0.3 0.6  Body mass index –0.28 ± 0.23 0.2 –0.18 ± 0.23 0.4 0.5 Preoperative status  NYHA class –0.41 ± 0.046 <0.0001 –0.076 ± 0.052 0.14 <0.001 Cardiac comorbidity  Left ventricular function –0.026 ± 0.052 0.6 –0.15 ± 0.057 0.007 0.009  Preoperative atrial fibrillation 0.60 ± 0.52 0.2 0.56 ± 0.53 0.3 0.5  Previous myocardial infarction –0.14 ± 0.11 0.2 –0.19 ± 0.13 0.14 0.3 Noncardiac comorbidity  History of smoking 0.21 ± 0.13 0.09 –0.019 ± 0.13 0.9 0.06 Primary surgery  At Cleveland Clinic 1.2 ± 0.15 <0.0001 –0.23 ± 0.14 0.10 <0.0001  LITA to diagonal 0.61 ± 0.40 0.13 0.52 ± 0.41 0.2 0.3  RITA to LCx 2.0 ± 0.56 0.0003 1.5 ± 0.57 0.007 0.0007  RITA to diagonal 2.1 ± 1.1 0.06 2.1 ± 1.1 0.06 0.15  RITA to RCA 1.1 ± 0.34 0.0009 0.77 ± 0.34 0.03 0.004  SVG to LAD 2.4 ± 1.1 0.03 1.4 ± 1.1 0.2 0.02  SVG to LCx 1.2 ± 0.16 <0.0001 0.56 ± 0.17 0.001 <0.0001  SVG to diagonal 0.24 ± 0.15 0.12 0.21 ± 0.16 0.2 0.3  SVG to RCA 1.1 ± 0.15 <0.0001 0.54 ± 0.16 0.001 <0.0001 Index angiogram  Interval from primary CABG to angiogram –0.099 ± 0.013 <0.0001 –0.096 ± 0.013 <0.0001 <0.0001  Date of angiogram 15 ± 2.4 <0.0001 –56 ± 5.4 <0.0001 <0.0001  Native LMT disease –0.76 ± 0.16 <0.0001 –1.2 ± 0.17 <0.0001 <0.0001  Native LAD disease 0.24 ± 0.29 0.4 0.27 ± 0.31 0.4 0.6  Native LCx disease –0.32 ± 0.33 0.3 0.14 ± 0.35 0.7 0.2  Native RCA disease 0.55 ± 0.30 0.07 0.43 ± 0.33 0.2 0.2  Stenosis in graft to RCA –0.54 ± 0.50 0.3 –0.30 ± 0.52 0.6 0.5  Stenosis in graft to diagonal –0.60 ± 0.18 0.001 –0.45 ± 0.20 0.02 0.005  Stenosis in graft to LCx –1.7 ± 0.39 <0.0001 –0.76 ± 0.41 0.07 <0.0001  Jeopardized RCA system b –0.76 ± 0.52 0.14 –0.65 ± 0.53 0.3 0.3  Jeopardized LCx system b 0.48 ± 0.41 0.2 –0.35 ± 0.43 0.4 0.06 a (Age/50), exponential transformation. b Jeopardized systems were defined as the minimum of (1) maximum stenosis in the native vessel and (2) maximum stenosis in the graft.

CABG = coronary artery bypass grafting; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; LITA = left internal thoracic artery; LMT = left main trunk; NYHA = New York Heart Association; RCA = right coronary artery; RITA = right internal thoracic artery; SEM = standard error of the mean; SVG = saphenous vein graft.

	Discussion

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 
DR JOHN D. PUSKAS (Atlanta, GA): Perhaps you could answer my question about double mammary grafts. You commented on a single patent graft to the LAD. Do you have any data to share with us about the relative benefit for long-term survival or efficacy of medical management in patients who have two ITA grafts?

DR SUBRAMANIAN: That is an excellent question. Regarding the use of arterial grafts in this study, the incidence of use of an RITA (right ITA) or a radial graft was very low, at 2% to 6%. The study period ended in 2000, primarily due to limitations with the PI (percutaneous intervention) follow-up data. We don't have specific data on medical management for patients with double ITA grafts. However, the literature and our data suggest that the increasing use of arterial grafts at primary operation reduces the need for reoperation.

DR VALAVANUR SUBRAMANIAN (New York, NY): I enjoyed the paper. I just have one question. In the reoperative setting what is your strategy for using an additional arterial graft? Does that have an influence on survival? For example, a right mammary graft to the circumflex?

DR S. SUBRAMANIAN: This study will have some important follow-up analyses, and that is one of them. We have not yet completed subgroup analyses to determine the outcomes with arterial grafts at reoperation when the LITA-LAD is patent. Presently, we know that revascularization for non-LAD ischemia does not improve survival, but medical and surgical management continue to improve. So the natural extension would be to look at using arterial grafts (which have better patency than vein grafts at primary operations) versus best medical management to determine the impact, but we don't have any data at this point.

DR DIMITRI NOVITZKY (Tampa, FL): Interesting presentation. My question is, having a patent mammary artery to the LAD, what approach do you use for redo CABG? Do you use alternative approaches such as left thoracotomy, or an axillary anterior thoracotomy for a redo of the circumflex or the distal left anterior descending coronary arteries? Avoiding the redo sternotomy is safer, to a midline redo sternotomy; do you approach the right artery via alternative approaches to the median sternotomy? Could you please elaborate?

DR SUBRAMANIAN: We generally favor a redo median sternotomy. As previously discussed, there are a number of techniques for repeat safe sternal entry. Using these techniques, mortality for reoperative coronary surgery at Cleveland Clinic is now below 2%.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 
This study was supported in part by the Kenneth Gee and Paula Shaw, PhD, Chair in Heart Research, held by Dr. Blackstone.

	References

Top Abstract Introduction Patients and Methods Results Comment Appendix Table 1 Appendix Table 2 Discussion Acknowledgments References

 

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				Writing Committee Members, G. N. Levine, E. R. Bates, J. C. Blankenship, S. R. Bailey, J. A. Bittl, B. Cercek, C. E. Chambers, S. G. Ellis, R. A. Guyton, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions Circulation, December 6, 2011; 124(23): e574 - e651. [Full Text] [PDF]

				Writing Committee Members, G. N. Levine, E. R. Bates, J. C. Blankenship, S. R. Bailey, J. A. Bittl, B. Cercek, C. E. Chambers, S. G. Ellis, R. A. Guyton, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions Circulation, December 6, 2011; 124(23): 2574 - 2609. [Full Text] [PDF]

				Writing Committee Members, L. D. Hillis, P. K. Smith, J. L. Anderson, J. A. Bittl, C. R. Bridges, J. G. Byrne, J. E. Cigarroa, V. J. DiSesa, L. F. Hiratzka, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Circulation, December 6, 2011; 124(23): e652 - e735. [Full Text] [PDF]

				Writing Committee Members, L. D. Hillis, P. K. Smith, J. L. Anderson, J. A. Bittl, C. R. Bridges, J. G. Byrne, J. E. Cigarroa, V. J. DiSesa, L. F. Hiratzka, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Circulation, December 6, 2011; 124(23): 2610 - 2642. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Sreekumar Subramanian Joseph F. Sabik, III Edward R. Nowicki Eugene H. Blackstone Bruce W. Lytle Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Subramanian, S. Articles by Lytle, B. W. Search for Related Content PubMed PubMed Citation Articles by Subramanian, S. Articles by Lytle, B. W. Related Collections Coronary disease