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Ann Thorac Surg 2007;83:993-1001
© 2007 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Outcomes Associated With the Use of Secondary Prevention Medications After Coronary Artery Bypass Graft Surgery

Abhinav Goyal, MD, MHSa, John H. Alexander, MD, MHSa,*, Gail E. Hafley, MSa, Stacy H. Graham, MDa, Rajendra H. Mehta, MD, MSa, Michael J. Mack, MDb, Randall K. Wolf, MDc, Lawrence H. Cohn, MDd, Nicholas T. Kouchoukos, MDe, Robert A. Harrington, MDa, Daniel Gennevois, MDf, C. Michael Gibson, MDg, Robert M. Califf, MDa, T. Bruce Ferguson, Jr, MDh, Eric D. Peterson, MD, MPHa, PREVENT IV Investigators

a Duke Clinical Research Institute and Division of Cardiology, Duke University Medical Center, Durham, North Carolina
b Cardiothoracic Surgery Associates of North Texas, Dallas, Texas
c University of Cincinnati Surgeons, Inc, Cincinnati, Ohio
d Division of Cardiac Surgery, Brigham and Women’s Hospital, Boston, Massachusetts
e Division of Cardiovascular and Thoracic Surgery, Missouri Baptist Medical Center, St. Louis, Missouri
f Corgentech, Inc, San Francisco, California
g Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
h Division of Cardiothoracic Surgery, Brody School of Medicine at Eastern Carolina University, Greenville, North Carolina

Accepted for publication October 16, 2006.

* Address correspondence to Dr Alexander, Duke University Medical Center, DUMC Box 3850, Durham, NC 27710 (Email: john.h.alexander{at}duke.edu).


Drs Gennevois, Alexander, and Gibson disclose that they have a financial relationship with Corgentech, Inc.

 

   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Secondary prevention medications are beneficial after acute coronary syndromes, but these benefits are less clear after coronary artery bypass graft surgery. We investigated whether greater use of secondary prevention medications after coronary artery bypass graft surgery is associated with improved clinical outcomes.

Methods: Patients undergoing coronary artery bypass graft surgery in the PREVENT IV trial (n = 2970) were surveyed for use of antiplatelet agents, ß-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and lipid-lowering agents after hospital discharge and at 1 year. Patients were categorized based on their percentage use of indicated medications after hospital discharge. Cox modeling was used to determine the association between medication use categories and rates of death or myocardial infarction through 2 years after adjustment for clinical factors, the number of indicated medications, and treatment propensity.

Results: Rates of use of antiplatelet agents and lipid-lowering agents were high at discharge and at 1 year, but use of ß-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was suboptimal. There was a stepwise association between medication use at discharge and patient outcomes (p for trend = 0.014). Patients taking 50% or less of indicated medications at discharge had a significantly higher 2-year rate of death or myocardial infarction (8.0% versus 4.2%; adjusted hazard ratio, 1.69; 95% confidence interval, 1.12 to 2.55; p = 0.013) than those taking all indicated medications.

Conclusions: Greater use of indicated secondary prevention medications after coronary artery bypass graft surgery is associated with a lower 2-year rate of death or myocardial infarction. These data underscore the importance of appropriate secondary prevention measures to improve long-term clinical outcomes after coronary artery bypass graft surgery.

Coronary artery bypass graft surgery (CABG) is among the most commonly performed procedures in the United States, with almost 500,000 CABG operations performed annually [1]. During the past two decades, patients undergoing CABG have had an increasing burden of comorbidities and cardiac risk factors [2, 3]. Despite the higher-risk profile of patients undergoing CABG, perioperative mortality has declined in CABG patients as a result of advances in operative techniques and improvements in the in-hospital management of CABG patients [2]. However, long-term survival after CABG has not improved during the past two decades [3], underscoring the need for improvements in secondary prevention strategies in these patients [4].

The use of secondary prevention medications, such as antiplatelet agents [5, 6], angiotensin-converting enzyme (ACE) inhibitors [7, 8], ß-blockers [9], and lipid-lowering therapy [10, 11], have each been associated with a lower rate of adverse cardiac events in patients after CABG. However, whether greater use of multiple secondary prevention medications after CABG is associated with improved clinical outcomes is unknown. Recent studies have reported that appropriate medical therapies are underutilized after CABG surgery [12, 13]; however, they did not report the impact of medication use on clinical outcomes. In the PRoject of Ex-vivo Vein graft ENgineering via Transfection (PREVENT) IV trial of 3,014 patients undergoing first CABG surgery [14, 15], patients were surveyed for use of medications just after hospital discharge and at 1 year, and were followed for 2 years after CABG for the occurrence of death or myocardial infarction (MI). These data provide a unique opportunity to investigate the association between the use of multiple secondary prevention medications and clinical outcomes after CABG.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
The PREVENT IV Trial
Patients included in this study were enrolled in the PREVENT IV trial, the design of which has been previously described [14, 15]. Briefly, PREVENT IV was a multicenter, randomized, double-blind, placebo-controlled trial of 3,014 patients undergoing first CABG investigating whether the ex vivo treatment of vein grafts with the E2F transcription factor decoy, edifoligide (Corgentech Inc, San Francisco, CA), prevents vein graft failure and improves clinical outcomes [15]. All 3,014 patients are being followed for death and MI through 5 years. Follow-up through 2 years has been completed, and all suspected clinical events have been adjudicated by an independent, blinded, clinical events committee. Institutional review board approval was obtained at all sites, and all patients gave written informed consent before participation in the trial. The PREVENT IV trial was designed and directed by an academic steering committee that included representatives from the Society of Thoracic Surgeons, and was coordinated by the Duke Clinical Research Institute (Durham, NC) [15].

Medication Use
Discharge medication use was collected between hospital discharge and 30 days by contacting patients by phone or in person during the first follow-up clinic visit within 30 days of CABG. Medications were collected and then coded into classes, including antiplatelet agents (aspirin or clopidogrel), ACE inhibitors or angiotensin receptor blockers (ARBs), ß-blockers, and lipid-lowering medications (statins or any nonstatin lipid-lowering agent). At 1-year follow-up, patients were again contacted by mail to document which medications they were taking. Those who did not respond by mail were subsequently contacted by phone to obtain medication use at 1 year.

Patient Population
Patients were included in this study if they were alive and free from MI at the time of 30-day follow-up. Of the 3,014 patients enrolled in PREVENT IV, 2,970 were included for rates of use and associated outcomes (Fig 1). Patients were then stratified on the basis of whether or not they were ideal candidates for each of the four classes of secondary prevention medications at the time of hospital discharge based on having a class IA indication for these medications according to the American College of Cardiology/American Heart Association guidelines for CABG [16] or for chronic heart failure in adult patients [17], and having no relative or absolute contraindications for that medication (Appendix). The numbers of patients considered ideal and nonideal candidates for each medication class are shown in Figure 1.


Figure 1
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  		Fig 1. Patient population. See Appendix for the definitions of ideal candidates for classes of evidence-based secondary prevention medications. (ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; MI = myocardial infarction; PREVENT IV = PRoject of Ex-vivo Vein graft ENgineering via Transfection IV trial.)

 
Patients were also categorized into three comparison groups on the basis of the number of indicated secondary prevention medications that a patient was taking at hospital discharge divided by the number of medications for which a patient had a class IA indication according to the American College of Cardiology/American Heart Association guidelines. The three comparison groups included patients taking half or fewer of the indicated medications at hospital discharge, patients taking more than half but not all of the indicated medications, and patients taking all indicated medications (Table 1). These comparison groups were defined before statistical analyses and were chosen to ensure a sufficient number of patients in each group to allow meaningful between-group comparisons.


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  		Table 1 Assignment of Comparison Groups on Basis of Composite Medication Use
 
Data Analysis and Statistical Methods
Baseline characteristics were summarized within comparison groups by medians and 25th and 75th percentiles for continuous variables, and by percentages for categorical variables. To determine the association between the use of each individual medication class at discharge and 2-year death or MI, four covariate-adjusted models were developed (one for each medication class) using Cox proportional hazards regression. Each of these four models was adjusted for age, sex, recent MI (within 30 days of CABG), history of congestive heart failure, creatinine clearance, history of diabetes, and use of the other three classes of medications. In addition, each model was also adjusted for variables associated with the use of that specific medication class using propensity scores. (The propensity to be taking antiplatelet agents was not considered because only 3% of patients were not taking antiplatelet agents.) Propensity scores were developed from binary logistic regression models and were represented in the final Cox proportional hazards models by a variable consisting of the linear score or logit. Finally, to account for the potential differential effect of medications on outcomes in patients who were and were not ideal candidates for these medications, we created a binary variable for ideal candidacy for each medication class (except that this was not done for antiplatelet agents because 98% of patients were considered ideal candidates for antiplatelet therapy). We then tested for interactions between the ideal candidate variables and use of each of the medication classes. All of these interaction terms had a probability of 0.10 or less (defined a priori), and therefore hazard ratios and 95% confidence intervals were presented separately for ideal and nonideal patients for each medication class.

To determine whether more complete use of multiple secondary prevention medications at discharge was associated with a lower rate of death or MI at 2 years, we used the Kaplan–Meier method to determine the unadjusted 2-year rate of death or MI among patients in each comparison group defined in Table 1. We then created another Cox proportional hazards model for 2-year death or MI in which patients taking half or fewer of the indicated medications at hospital discharge and patients taking more than half but not all indicated medications were compared with the reference group of patients taking all indicated medications at discharge. This model was adjusted for age, sex, recent MI, history of congestive heart failure, creatinine clearance, history of diabetes, the propensity to be taking all indicated medications, and the number of drugs for which patients had an ideal indication.

All analyses were performed using SAS statistical software, version 8.2 (SAS Inc, Cary, NC), and a probability value of 0.05 or less was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Baseline Characteristics and Rates of Use of Secondary Prevention Medications
The demographic and medical history profile of patients in the PREVENT IV (Table 2) were comparable with those of "real-world" CABG patients registered in The Society of Thoracic Surgeons National Database in 2002 [14]. Rates of use of medications were documented in 99.5% of the PREVENT IV cohort after hospital discharge, and in 96.0% of patients who were alive at 1 year. At hospital discharge, rates of use of antiplatelet agents, ß-blockers, and lipid-lowering therapies were high among ideal candidates for these medications (>80%), but use of ACE inhibitors or ARBs was low (<50%; Fig 2). At 1 year, rates of use of antiplatelet agents and lipid-lowering agents remained high (>80%), but use of ß-blockers dropped to less than 80%. Use of ACE inhibitors or ARBs increased by almost 15%, but their use still remained suboptimal (<60%; Fig 2). Among patients taking antiplatelet agents at 1 year, 97% had also taken these agents at hospital discharge; only 3% were started on them de novo during the first year of follow-up. Similarly, 93% of patients taking ß-blockers and 87% of patients taking lipid-lowering drugs at 1 year had also taken them at discharge, indicating that most of the use of secondary prevention medications at 1 year was among patients who had taken these agents at hospital discharge. Among patients taking ACE inhibitors or ARBs at one year, 62% had also taken them at discharge, and 38% started taking them during the first year of follow-up.


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  		Table 2 Baseline Characteristics Among Patients Categorized by Composite Medication Use
 

Figure 2
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  		Fig 2. Rates of use of secondary prevention medications among postcoronary artery bypass graft surgery patients after hospital discharge and at 1 year. Rates of medication use are shown for ideal candidates for each medication class. (ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker.)

 
Discharge Use of Individual Medication Classes and Clinical Events at 2 Years
Of the 2,970 patients in the study, 147 (4.9%) died or had an MI through 2 years, of whom 135 had an event during the first year and 12 during the second year of follow-up. The use of antiplatelet agents at discharge was associated with a lower adjusted hazard of death or MI (Table 3). Use of ß-blockers was associated with a trend toward a lower hazard of death or MI among ideal patients, but not among nonideal patients. Use of ACE inhibitors or ARBs and of lipid-lowering agents was not associated with clinical outcomes among ideal candidates for these medications.


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  		Table 3 Association Between Use of Each Class of Medications at Hospital Discharge and Death or Myocardial Infarction at 2 Years
 
Composite Medication Use and Clinical Events
Sixty-five percent (1,924 of 2,970) of post-CABG patients were taking all indicated medications after discharge (Table 4). There was a stepwise association between more complete use of secondary prevention medications at discharge and improved patient outcomes at 2 years (p for trend = 0.014). Compared with patients taking all indicated medications at discharge, patients taking half or fewer of the indicated medications had nearly twice the unadjusted rate of death or MI at 2 years (8.0% versus 4.2%), and an adjusted hazard ratio for death or MI of 1.69 (95% confidence interval, 1.12 to 2.55; p = 0.013).


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  		Table 4 Association Between Composite Medication Use and Death or Myocardial Infarction at 2 Years
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
This study from a contemporary CABG trial cohort of almost 3,000 patients demonstrates that rates of use of secondary prevention medications in patients with ideal indications for these therapies are high for antiplatelet agents and lipid-lowering agents, but suboptimal for ß-blockers and ACE inhibitors or ARBs. This study also demonstrates for the first time that the use of multiple secondary prevention medications after CABG is associated with improved clinical outcomes, thus underscoring the importance of ensuring appropriate secondary prevention measures after CABG.

Rates of Use of Secondary Prevention Medications
In PREVENT IV, rates of use of antiplatelet agents, ß-blockers, and lipid-lowering agents were relatively high after discharge after CABG, but use of ACE inhibitors or ARBs was suboptimal. Rates of use of secondary prevention medications in PREVENT IV were notably higher than those reported from "real-world" CABG patients from the 2002 Society of Thoracic Surgeons National Database [14] (in which only 80%, 68%, 28%, and 55% of patients were receiving aspirin, ß-blockers, ACE inhibitors, and lipid-lowering therapy, respectively, at discharge), and from elderly patients who underwent CABG after acute MI in the Centers for Medicare/Medicaid Services database [12] (in which 88%, 62%, and 35% of patients with proven indications for aspirin, ß-blockers, or lipid-lowering drugs, respectively, actually received these drugs). These "real-world" registry data support the need to improve discharge processes to increase prescription rates for secondary prevention medications after CABG.

We were able to capture 1-year medication use data in more than 95% of the PREVENT IV patients who were alive at 1 year. Rates of use of secondary prevention medications were surprisingly well maintained at 1-year follow-up, particularly for antiplatelet and lipid-lowering agents, and use actually increased substantially for ACE inhibitors and ARBs. Furthermore, the overwhelming majority of patients taking secondary prevention agents at 1 year had also taken these agents soon after hospital discharge, and only a very small percentage of patients not taking these medications at discharge were started on these drugs de novo during the first year of follow-up. These data clearly attest to the critical importance of initiating appropriate secondary prevention therapies soon after CABG to ensure long-term adherence to these proven therapies.

Medication Use and Clinical Events
The benefit of antiplatelet therapy after CABG has been well established [5, 6]. In our study, the use of antiplatelet agents was associated with a 56% lower hazard of death or MI at 2 years. However, as only a very small proportion of the overall cohort (3%) was not on an antiplatelet agent at hospital discharge, it is likely that the lack of use of antiplatelet agents was mainly a marker of serious comorbidities that led to a high clinical event rate.

Use of ß-blockers at discharge in those with a proven indication (ie, prior MI or symptomatic congestive heart failure with left ventricular systolic dysfunction) was associated with a trend toward a lower hazard of death or MI at 2 years after CABG. These findings are consistent with studies demonstrating the survival advantage conferred by ß-blockers on patients after acute MI [18, 19] and congestive heart failure with left ventricular dysfunction [20, 21]. However, we did not demonstrate an association between ß-blocker use and improved outcomes in post-CABG patients who were not ideal candidates for these medications (ie, in most routine CABG patients). Although observational studies have suggested that preoperative ß-blocker use is associated with reduced rates of morbidity and mortality after CABG [22, 23], a randomized placebo-controlled trial demonstrated no clinical benefit from ß-blocker use for 2 years after CABG in a relatively low-risk group of post-CABG patients (similar to the PREVENT IV cohort) [24].

Use of ACE inhibitors or ARBs was not associated with improved 2-year outcomes in post-CABG patients in our study [16, 17]. The benefit of ACE inhibitors in patients with left ventricular systolic dysfunction is well established [25, 26]; however, the median ejection fraction (0.50) in our study was higher than that of patients in these prior studies. Use of ACE inhibitors in patients with prior MI [27, 28] or at high-risk for vascular events [29, 30] has also been shown to be beneficial, but two recent trials of lower-risk coronary heart disease patients with preserved left ventricular function [31–33], including one in post-CABG patients [32, 33], failed to demonstrate a reduction in mortality or other vascular events with ACE inhibition.

Use of lipid-lowering therapy in our study was also not associated with improved 2-year outcomes. Although several trials have demonstrated that statins reduce mortality and other vascular events compared with placebo among patients with coronary heart disease [34, 35], a clinical benefit was not apparent during the first few years of follow-up. Furthermore, in a randomized trial of aggressive-intensity versus moderate-intensity lipid-lowering therapy in post-CABG patients, aggressive lipid-lowering therapy did not reduce the incidence of death or MI after 4 years [10]. Similarly, the 2-year follow-up of PREVENT IV may not be of sufficient duration after CABG to detect a clinical benefit from lipid-lowering therapy.

It is noteworthy (but not surprising) that we found an association between composite medication use and clinical outcomes, but not between the use of most individual medications and subsequent outcomes. Although almost 3,000 patients are included in our study, we did not expect to have sufficient power to detect an association between individual medications and clinical outcomes after only a 2-year follow-up period. However, it is reasonable that we detected an association between more complete use of multiple secondary prevention medications and clinical outcomes, inasmuch as the effect of any one secondary prevention medication is additive to the effect of others. A strong association between combinations of medications and clinical outcomes, despite an absent association between certain individual medications and outcomes, has been previously reported in ischemic heart disease patients [36].

Composite Medication Use and Clinical Events
Greater use of multiple indicated secondary prevention medications at discharge was associated with a lower rate of death or MI at 2 years. The number of secondary prevention therapies used in patients with coronary artery disease has been shown to predict improved outcomes in patients after coronary angiography [37], after percutaneous coronary intervention [38], and after acute coronary syndromes [39, 40]. Our study extends these prior observations by demonstrating that greater use of multiple indicated medications is also associated with improved outcomes after CABG as well. Despite advances in intraoperative technique and postoperative management, long-term outcomes after CABG have not improved in the past two decades [3, 4]. Recent reports documenting the underutilization of secondary prevention medications after CABG [12, 13] have identified a potential area in which improvement could lead to better long-term outcomes in post-CABG patients [4]. This study provides the needed complementary evidence that increased use of indicated medications at hospital discharge is associated with improved clinical outcomes after CABG surgery.

Limitations
First, our data are from a clinical trial database and thus may not accurately reflect the impact of medication use on outcomes in the "real world." However, a comparison of patients in PREVENT IV and patients undergoing first CABG from The Society of Thoracic Surgeons National Database suggests that the baseline demographics, medical history, and burden of coronary artery disease are remarkably similar [14]. Second, we evaluated the association between composite medication use at a single time period (hospital discharge) and 2-year clinical outcomes. However, we could not evaluate the effect of consistent medication use between discharge and 1 year on 2-year outcomes, as there were only 12 clinical events that occurred after the 1-year medication survey. We did, however, demonstrate that the great majority of use of secondary prevention medications at 1 year was among those taking these medications at discharge, and thus we believe a similar association would likely be found between more consistent use of medications and improved long-term clinical outcomes. Finally, although we adjusted for known confounders and treatment propensity, these data are observational in nature and thus may not account for the influence of unmeasured confounders. Therefore, it is possible that the observed association between more complete secondary prevention medication use and improved clinical outcomes may not be directly attributable to the medications’ effects, but may rather reflect better concomitant medical care, higher rates of other preventive measures (such as smoking cessation), or higher socioeconomic or educational status in the group taking all indicated medications. Nevertheless, this study provides evidence that increased use of indicated medications at hospital discharge is a valid measure of quality of care in patients undergoing CABG surgery.

Conclusions
Long-term use of proven secondary prevention medications in post-CABG patients is strongly linked to their use after hospital discharge, and greater use of these medications after CABG is associated with lower rates of subsequent death or MI. Strategies must be implemented to ensure greater adherence to appropriate secondary prevention therapies to improve long-term clinical outcomes after CABG.


   Appendix
 
Definition of Ideal Candidates for Secondary Prevention Medications After Coronary Artery Bypass Graft Surgery
Patients were considered ideal candidates for each class of evidence-based medications only if they met the following class IA (class I, level A) indications according to the American College of Cardiology/American Heart Association (ACC/AHA) CABG [16] or chronic heart failure guidelines [17], and did not have any relative or absolute contraindications for these medications that are listed below. Class I refers to those indications for which there is evidence or general agreement that a given medication is useful and effective, and level A indicates that the evidence supporting these recommendations are derived from multiple randomized clinical trials [16, 17]. The list of class IA indications for each group of medications is followed by a citation for the specific ACC/AHA guideline from which the indication was derived. (ACE = angiotensin converting enzyme; CABG = coronary artery bypass graft surgery; NYHA = New York Heart Association Class; PREVENT IV = PRoject of Ex-vivo Vein graft ENgineering via Transfection IV trial.)

I Antiplatelet agents
A Ideal candidates (class IA indications): all post-CABG patients [16] in the PREVENT IV cohort
B Exception (relative contraindication): patients who had bleeding requiring reoperation before hospital discharge

II ß-Blockers
A Ideal candidates (class IA indications)
1 Any history of myocardial infarction [17]
2 Reduced preoperative ejection fraction (<0.45) with NYHA class II or III symptoms [17]

B Exceptions (relative or absolute contraindications)
1 NYHA class IV symptoms at baseline
2 Perioperative cardiogenic shock
3 Perioperative use of an intraaortic balloon pump (for hypotension)
4 Any history of chronic lung disease
5 Documented acute respiratory distress syndrome in between CABG and discharge
6 Resting heart rate of 55 beats per minute or less in the absence of a cardiac pacemaker


III ACE inhibitors or angiotensin receptor blockers
A Ideal candidates (class IA indications)
1 Any history of myocardial infarction [17]
2 Reduced preoperative ejection fraction (<0.45) with NYHA class II through IV symptoms [17]

B Exceptions (relative or absolute contraindications)
1 Renal failure (documented history before CABG, documented occurrence after CABG, or serum creatinine of 2.0 mg/dL or greater during hospitalization before or after CABG)
2 Perioperative cardiogenic shock
3 Perioperative use of an intraaortic balloon pump


IV Lipid-lowering therapy
A Ideal candidates (class IA indications): history of hypercholesterolemia or low-density lipoprotein cholesterol of 100 mg/dL or greater at baseline [16]
B Exception (relative or absolute contraindications): history of liver disease


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
The PREVENT IV trial was funded by Corgentech, Inc (San Francisco, California), but Corgentech, Inc had no involvement in the analysis of these data. This manuscript was funded by the Duke Clinical Research Institute.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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