Impact of Functional Testing Results on Prescription Patterns of Anti-Anginal Medication after Coronary Artery Bypass Graft Surg

Coronary artery bypass graft surgery (CABG) relieves anginal symptoms and decreases morbidity and mortality in patients suffering from coronary artery disease (CAD).^1,2 Unless comorbid diseases are present, guidelines do not recommend the routine use of anti-anginal medication post-CABG.^3,4 However, previous studies suggest that anti-anginal medication is not significantly reduced following CABG. It is also unclear whether functional testing results have an impact on post-CABG prescription patterns. Functional testing is often used to identify graft occlusion, native coronary artery disease progression, and to quantify any residual ischemia. Thus, a positive functional test may suggest the need for more intensive medical therapy or revascularization procedures. In contrast, a negative functional test suggests that anti-anginal medication use could be decreased. In this study, we examined patients enrolled in the ROSETTA-CABG Registry to determine how post-CABG functional testing results affect prescription patterns of anti-anginal medication. Methods Patient population. A total of 408 patients were enrolled in the Routine Versus Selective Exercise Treadmill Testing after Coronary Artery Bypass Graft Surgery (ROSETTA-CABG) Registry between May 30, 1999 and May 30, 2002. Twelve-month follow up was complete by May 2003. Patients were enrolled in the study immediately after their CABG, but before they were discharged from the hospital. The study was approved by the Research and Ethics Committee at the institutions involved, and written informed consent was obtained before patients were enrolled. Inclusion criteria included a first successful CABG, with a successful CABG being defined as one in which all ischemic areas were thought to be revascularized and the patient had no major in-hospital events (e.g., perioperative myocardial infarction [MI], stroke, need to return to the operating room). Moreover, only patients with isolated CABG surgery were eligible. Patients who underwent valve surgery, aortic repair, and so forth, were not enrolled. Patients were excluded if they: 1) were participating in conflicting clinical studies; 2) had contradictions to repeat cardiac procedures (cardiac catheterization, percutaneous coronary intervention [PCI], repeat CABG); 3) had contradictions or inability to undergo follow-up functional testing; 4) had a future revascularization procedure planned; 5) had a medical condition with a prognosis Baseline clinical and procedural characteristics. Baseline clinical and procedural data were collected at the time of patient entry. Baseline information included medication therapy, demographic data, as well as clinical characteristics such as comorbid conditions and prior procedures. Procedural characteristics included the primary indication for CABG as well as the numbers and types of bypass grafts. Twelve-month Follow up. There was no medical therapy protocol. Physicians were free to treat patients with medical therapy as they saw fit. Clinical follow-up data were obtained 12 months after CABG. The study nurse at the patient’s clinical center conducted a telephone interview with the patient to determine if post-CABG functional testing took place and to document if any endpoints occurred. In addition to the telephone interview, the nurse contacted the patient’s cardiologist (and other physicians if necessary) for 12-month follow-up information. If the patient underwent functional testing during the 12-month follow-up period, documentation of the type and results of the testing were obtained. If tests occurred at other institutions, the research nurse also contacted that institution to obtain the appropriate documentation. A functional test was defined as one of the following: exercise treadmill testing, stress echocardiography, stress nuclear perfusion imaging and others, such as positron emission tomographic (PET) imaging. Some physicians opted for a routine functional testing strategy, while others employed a symptom-driven strategy. Functional testing strategy was defined by the reason for the first functional test after the CABG. The patient was considered to have had routine functional testing if the first functional test was performed as a routine follow up. In contrast, patients were categorized in the selective group if the first functional test was performed for a clinical indication or if they did not undergo functional testing. Statistical analysis. We examined the use of anti-anginal therapy at the time of the index CABG and at 12 months. Specifically, we compared the rate of use of beta blockers, calcium channel blockers, nitrates (oral or patch), as well as combinations of anti-anginal therapy. Monotherapy was defined as the use of only one of the three anti-ischemic medications, double therapy as the combination of any two anti-anginal medications, and triple therapy as the use of all three anti-anginal medications. We then examined the 146 patients who underwent a functional test during the 12-month period post-CABG. For these patients, we compared the rates of anti-anginal use after CABG with respect to having a positive functional test result (electrically positive, clinically positive, or by imaging with a moderate or large area of ischemia at 12 months), a negative test or an indeterminate test. The same analyses were performed excluding patients with a prior MI and a history of congestive heart failure, because these conditions are indications for beta blocker use. Similarly, we repeated the analyses excluding patients with hypertension and radial grafts at baseline because this is a common indication for beta blocker and calcium channel blocker use. Finally, analyses were performed to identify which patients (those with positive, negative or indeterminate tests) began or stopped anti-anginal therapy during the follow-up period. Continuous data are presented as the mean ± standard deviation (SD), and were compared using the Student’s unpaired t-test. Dichotomous data are presented as percentages, and were compared with the Chi-square test. All statistical tests were two-tailed, and a p-value less than or equal to 0.05 was considered to be statistically significant. Results Baseline and procedural clinical characteristics. Table 1 shows the baseline clinical and procedural characteristics of the following: 1) the 146 patients with functional testing during the 12-month follow up; 2) the 246 patients without functional testing; and 3) all patients. Anti-anginal use after CABG. In general, rates of anti-anginal use after CABG varied little from discharge after the index procedure to 12 months post-CABG (Figure 1). There was, however, a trend toward a modest reduction in beta blocker use among all patients in the study (73% to 63%; p = 0.01). In contrast, calcium channel blocker and nitrate use was unchanged (20% vs. 18%; p = NS and 9% vs. 9%; p = NS, respectively). Similarly, the rates of combinations of anti-anginal therapy decreased minimally over the 12-month period. Patients may have been taking beta blockers or calcium channel blockers at 12 months due to prior conditions such as hypertension, prior MI or the presence of a radial graft. We therefore repeated the above analyses, excluding patients with these comorbid conditions (Table 2). The results did not change significantly after excluding patients with hypertension, a prior MI, or a radial graft, as well as those with all three conditions. Beta blocker use remained high in all cases: half of our patients on beta blockers continued this medication 12 months after CABG, with no indication. We found the greatest decrease in calcium channel blocker use in the subgroup of patients with no hypertension (15.2% vs. 8.3%, respectively; p p = NS). Functional testing results did not appear to impact strongly on the prescription patterns of beta blockers, calcium channel blockers or nitrates (Table 3). Among the 392 patients, 146 underwent functional testing during the 12-month period post-CABG. Most of the functional tests were exercise treadmill tests (70%), with a minority being stress perfusion imaging studies (20%), stress echocardiographic studies (6%), or other tests (4%). Among the 146 patients, 17% (N = 25) had positive tests, 69% (N = 100) had negative tests, and 14% (N = 21) had indeterminate tests. Both beta blocker and calcium channel blocker use did not increase from discharge to 12 months following a positive test (84% vs. 80%; p = NS and 16% vs. 16%; p = NS, respectively), but nitrate use increased seven-fold (4% vs. 28%; p = 0.03). Following negative functional test results, there was a significant reduction in beta blocker use (84% vs. 66%; p = 0.0002) and in calcium channel blocker use (33% vs. 21%; p = 0.03), while nitrate use remained unchanged (4% vs. 4%; p = NS). The rates of monotherapy at discharge and at 12 months were parallel to those of beta blocker use. Rates of double and triple therapy were low throughout the follow-up period. Among patients who had indeterminate test results, anti-anginal medication use was unchanged from discharge to 12 months after CABG. Finally, patients who did not undergo any functional testing demonstrated minimal changes in anti-anginal therapy post-CABG, except for the common trend in the reduction of beta blocker use (67% vs. 58%; p = 0.05). We performed this same analysis, excluding patients with prior hypertension, prior MI and both, and again observed minor variations in medical therapy. The lack of change in anti-anginal therapy from discharge to 12 months could represent similar numbers of patients stopping and starting anti-anginal therapy. We therefore performed contingency analyses in order to clarify which patients began or stopped medical therapy during the follow-up period. Among the 146 patients who underwent functional testing, small numbers of of them began taking an anti-anginal medication during the follow-up period (3% beta blockers, 9% calcium channel blockers and 7% nitrates). Similarly, few patients stopped anti-anginal medications that they were receiving at discharge (17% beta blockers, 17% calcium channel blockers and 3% nitrates). Thus, the vast majority of patients remained on the same medical regimen throughout the follow-up period. Functional testing results did not appear to determine whether medical therapy was started or stopped. Discussion We undertook the present study in order to determine whether functional testing results have an impact on prescription patterns of anti-anginal medication post-CABG. We found that functional testing results have little impact on the prescription patterns of anti-anginal agents post-CABG. We confirmed that there is little reduction in beta blocker, calcium channel blocker or nitrate use after successful revascularization, despite the relief of anti-anginal symptoms post-CABG. Furthermore, we noted that only nitrate use is increased in response to a positive functional test result, and that beta blockers appear to be only modestly reduced in response to a negative functional test result. It appears that physicians do not modify patients’ medication over the 12-month follow-up period post-CABG, even in response to functional test results. Subanalyses excluding patients with comorbid clinical conditions with indications for anti-anginal medication use (prior MI, hypertension and presence of a radial graft) did not show any difference in the observed results. Previous studies. We were unable to find previous studies that examined the impact of functional testing results on prescription patterns of anti-anginal medication post-CABG or the direct effect of these medications on all post-CABG patients. Furthermore, few studies have examined the short-term and long-term effects of anti-anginal therapy post-CABG. Previous studies mainly assessed the benefits of anti-anginal medication use among patients undergoing CABG after MI. However, one recent review examined cardiac medical therapy for post-CABG patients.⁵ Chen et al. showed beta blockers reduce mortality from 12% to 4% one year after CABG in elderly patients who had a prior MI.⁶ In contrast, in one analysis, post-CABG patients with a prior MI were randomized to metoprolol or placebo.⁷ There was no significant decrease in the rates of primary endpoints (death, nonfatal MI, unstable angina, CABG or PCI) between the two groups. Furthermore, the same patients were previously examined in a study conducted by Sjoland et al., and the only difference found between the two groups was that the placebo group experienced a higher score of chest pain.³ Also, most studies have shown beta blockers to be effective after a MI to decrease mortality, reduce the risk of a cardiac event and to control the severity of atrial fibrillation.^7–10 The American College of Cardiology and the American Heart Association (ACC/AHA) guidelines also recommend beta blocker therapy in patients with acute MI.¹¹ Thus, despite its beneficial effects, future studies are to be conducted to determine the direct effect of beta blockers on all post-CABG patients. Calcium channel blockers and nitrates are frequently used for the prevention of vasospasm of radial artery grafts.¹² However, only one randomized trial examined the effects of calcium channel blockers on post-CABG patients.⁴ Gaudino et al. examined the clinical and angiographic effects of calcium channel blocker use one year after CABG on radial graft patency. No significant differences were observed in the recurrence of angina, ischemia and cardiac deaths between patients who continued calcium channel blocker therapy and those who stopped the therapy. No evidence was found to employ the routine use of calcium channel blockers after CABG. Finally, no randomized controlled trials examining the effects of nitrates were found. The main effect of nitrates on patients after CABG is the treatment of angina. Thus, since post-CABG patients have low rates of angina after being fully revascularized, there is no reason why nitrate use should be high after CABG. Potential explanations for the lack of variation in medical therapy. The use of beta blockers for the prevention of future events and reduction in mortality has been well established in patients with a prior MI.^13–16 Therefore, we would not expect post-CABG beta blocker use to decrease to 0%. However, even after performing subanalyses excluding patients with a prior MI and patients with a history of hypertension, beta blocker use remained high throughout the follow-up period. Thus the persistent use of beta blockers after successful revascularization remains unexplained. Similarly, calcium channel blockers are often used in patients with a history of hypertension.¹³ However, calcium channel blocker use did not decrease significantly after a subanalysis excluding hypertensive patients was performed. Furthermore, nitrates have no indication for primary or secondary prevention other than the relief of angina symptoms.^13,17 Their continued use after successful revascularization, especially in patients with negative functional test results, remains unexplained. The lack of reduction in anti-anginal medication after CABG could be explained as a passive therapeutic approach on the part of physicians who may be reluctant to change medical therapy after patients have been discharged from CABG surgery.¹⁸ The cardiac surgeon performing the CABG does not appear to be recommending a cessation of anti-anginal medication use at the patient’s discharge from the hospital. During follow up, cardiologists are also reluctant to change the prescribed anti-anginal medications and do not appear to be decreasing their use 12 months after successful revascularization. Conclusion Our study was designed to examine the impact of functional testing results on prescription patterns following CABG. We found that there is a modest reduction in the use of beta blockers, calcium channel blockers and nitrates during the first 12 months after CABG. These results suggest that functional testing results during the first year post-CABG do not have a strong impact on prescription patterns of anti-anginal agents. The ACC/AHA guidelines should address this issue to help physicians stop specific medical therapy if it is not needed or to start medical therapy if test results are positive. Appendix A Investigator and Institution: P. Block: Academisch Ziekenhuis – Vrije Universiteit, Brussels, Belgium; M. Eisenberg: Jewish General Hospital, Montréal, Québec, Canada; T. Huynh, L. Pilote: Montréal General Hospital, Montréal, Québec, Canada; C. Lauzon: CHRA Thetford Mines, Thetford Mines, Québec, Canada; D. Fourchy: Département de Cardiologie – Hôpital Bichat-Claude Bernard, Paris, France; M-H. Mejan: Service de Cardiologie, Corbeil Essones, France; R. Chaudhry: Shaikh Zayed Postgraduate Medical Institute, Lahore, Pakistan; D. Robert: Victoria Hospital, Blackpool, Lancashire, United Kingdom; M. Del Core: Cardiac Catheterization Laboratory, Omaha, Nebraska, United States; R. Duerr: Idaho Cardiology Associates, Boise, Idaho, United States; E. Goudreau: Medical College of Virginia, Richmond, Virginia, United States; E. Lader: Mid Valley Cardiology, Kingston, New York, United States; H. Nguyen: Christiana Care Health Services, Newark, Delaware, United States; F. Rogers: Downriver Cardiology Consultants, PC, Trenton, Michigan, United States; J. Russell: Asheville Cardiology Associates, Asheville, North Carolina, United States; R. Siegel: CV Research, Gilbert, Arizona, United States.

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