Beta-Blocker Use is Not Associated With Slow Flow During Rotational Atherectomy

Abstract: Objectives. The purpose of this study was to investigate the association between beta-blocker use and slow flow during rotational atherectomy (RA). Background. RA is often performed as part of percutaneous coronary interventions for the treatment of calcified lesions; however, the procedure can be complicated by slow flow. Previous reports suggested that the use of beta-blockers was associated with slow flow during RA. Methods. A total of 186 patients who received RA were included, and 87 patients were on beta-blockers. The occurrence of slow flow was compared between the beta-blocker group (n = 87) and the non-beta-blocker group (n = 99). Multivariate logistic regression analysis was performed to investigate whether the use of beta-blockers was associated with slow flow. Results. The occurrence of slow flow was not different between the beta-blocker group (29.9%) and the non-beta-blocker group (24.2%; P=.39). The use of beta-blockers was not significantly associated with slow flow (odds ratio, 0.75; 95% confidence interval, 0.34-1.68; P=.49) after controlling for all potential confounding factors. Conclusions. There was no definitive association between slow flow and the use of beta-blockers during RA. There is no need to discontinue beta-blockers in patients receiving RA.  

J INVASIVE CARDIOL 2012;24(8):379-384

Key words: rotational atherectomy, percutaneous coronary intervention

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Rotational atherectomy (RA) is often performed as part of percutaneous coronary intervention (PCI) for the treatment of calcified lesions. However, diverse complications such as perforation, burr entrapment, or slow flow have been reported.^1-3 Slow flow during RA is not an uncommon event, with a reported incidence of 8%-12%,^3-5 and is often associated with adverse clinical outcomes.^6-8 Among previous reports on the determinants of slow flow during RA, Sharma et al reported that use of beta-blockers was associated with slow flow.³ Therefore, the use of beta-blockers is sometimes discouraged before RA. In fact, in recent prospective randomized studies on slow flow during RA, none of the study participants were on beta-blockers at the time of the procedure.^4,9 

Beta-blockers are useful for the medical treatment of coronary artery disease (CAD). Clinical guidelines based on randomized controlled trials recommend beta-blockers for CAD patients.^10-13 Although it may be reasonable to discontinue beta-blockers to prevent slow flow, there are some CAD patients in whom discontinuation of beta-blockers is inappropriate. Therefore, it is clinically important to determine whether beta-blockers should be discontinued before RA.

The role of RA in current PCI may be different from that in previous PCI. Lesion modification for stent deployment is a major indication of RA in current practice,^14,15 whereas the rate of stent deployment was only 9%-15% in the previous era of PCI.¹⁶ We hypothesized that there is no definitive association between slow flow and the use of beta-blockers in RA in current clinical practice. The purpose of this study was to investigate the association between slow flow during RA and the use of beta-blockers.

Methods

Patients and lesions. We identified consecutive patients from our PCI database who had RA between January 1, 2008 and April 30, 2011. Patients who were on beta-blockers during RA were defined as the beta-blocker group, and those who were not on beta-blockers were defined as the non-beta-blocker group. All patients had RA performed for coronary revascularization and had appropriate cine angiography to determine if slow flow occurred. Appropriate cine angiography required at least one angiogram without obstacles such as a balloon or microcatheter between the time of RA and stenting. Patients were excluded if there was no appropriate angiogram between the time of RA and stenting. Slow flow was defined as slow or absent distal runoff (Thrombolysis in Myocardial Infarction [TIMI] flow grade ≤2). The indications for RA in our institution are as follows: (1) moderate or severe calcified lesions; (2) diffuse lesions that were expected to be difficult to stent; and (3) ostial lesions. When treating the culprit lesions in acute coronary syndrome (ACS), RA is not used as first-line therapy; however, RA is used for the culprit lesion in ACS, if necessary.

Clinical criteria were defined as follows. Hypertension was defined as systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg, or medical treatment for hypertension. Diabetes mellitus was defined as hemoglobin A1c level >6.5% or treatment for diabetes mellitus. Hyperlipidemia was defined as total cholesterol level >220 mg/dL, low-density lipoprotein cholesterol level >140 mg/dL, or treatment for hyperlipidemia. Chronic renal failure was defined as serum creatinine level >2.0 mg/dL. Acute coronary syndrome was defined as ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), or unstable angina. Chronic total occlusion was defined as total occlusion ≥3 months. Reference diameter and lesion length were calculated by quantitative coronary angiographic analysis using offline, computer-based software (QAngio XA version 7.1, MEDIS Imaging Systems). The burr-to-artery ratio was defined as the final burr size divided by the reference diameter. This study was approved by the Institutional Review Board of Jichi Medical University Saitama Medical Center.

Rotational atherectomy procedure. RA was performed using standard techniques. Before the procedure, all patients received oral aspirin (at least 81 mg). Ticlopidine (200 mg) or clopidogrel (75 mg) was added when coronary stenting was performed. Intravenous heparin was used to achieve an appropriate activated coagulation time (>250 seconds). The lesion was crossed with a 0.009˝ guidewire. The rotablator burr was subsequently advanced over the wire to a position proximal to the lesion. The burr was activated and moved with a pecking motion. Individual burring runs were performed at a speed of 180,000-220,000 rpm with a caution to avoid a decrease >5000 rpm. We used two types of drug cocktails during RA. From the beginning of the study period (January 2008) to April 2010, we used a verapamil-based cocktail (verapamil 5 mg, isosorbide dinitrate 2.5 mg, heparin 10,000 units, and normal saline 500 mL). We switched from a verapamil-based cocktail to a nicorandil-based cocktail because the results of clinical studies favored nicorandil.^4,9 From April 2010 to the end of the study period (April 2011), we used a nicorandil-based cocktail (nicorandil 12 mg, isosorbide dinitrate 2.5 mg, heparin 10,000 units, and normal saline 500 mL). We did not use any glycoprotein IIb/IIIa inhibitors, which are not available in Japan. 

Statistical analysis. Data are presented as percentages for categorical variables and the mean ± standard deviation for continuous variables. The occurrence of slow flow was compared between the beta-blocker and non-beta-blocker groups. Patients, lesions, and procedural characteristics were also compared between the two groups. The Kolmogorov-Smirnov test was performed to determine if the continuous variables were normally distributed. Normally distributed continuous variables were compared using an unpaired student’s t-test. Otherwise, continuous variables were compared using a Mann-Whitney U-test. Categorical data were compared using the chi-square test. Multivariate logistic regression analysis was performed to investigate whether the use of beta-blockers was associated with slow flow after controlling for potential confounding factors. Odds ratios and 95% confidence intervals were calculated. In this logistic regression model, the dependent variable was slow flow, and independent variables were beta-blocker use and potential confounding factors that showed a marginal difference (P<.20) between the beta-blocker and non-beta-blocker groups. All of the variables were simultaneously adjusted in a single step. A P-value <.05 was considered statistically significant. All analyses were performed using statistical software, SPSS 13.0 for Windows (SPSS Inc).  

Results

Between January 1, 2008 and April 30, 2011, there were 224 consecutive patients treated by RA in our medical center. Thirty-eight patients were excluded because of the lack of appropriate angiograms to evaluate slow flow after RA. Thus, a total of 186 patients were included in this analysis. There were 87 patients in the beta-blocker group and 99 in the non-beta-blocker group. The patient characteristics are shown in Table 1. The prevalence of hypertension and previous myocardial infarction was significantly higher in the beta-blocker group. Although systolic and diastolic blood pressures before RA were not different between the two groups, heart rate before RA in the beta-blocker group was significantly lower than in the non-beta-blocker group. More than 80% of patients in the beta-blocker group were on either carvedilol or bisoprolol. Lesions and procedural characteristics are shown in Table 2. Although lesion length in the beta-blocker group was significantly longer than in the non-beta-blocker group, other characteristics were not significantly different.

Slow flow occurred in 50 (26.9%) of the 186 patients (26 in the beta-blocker and 24 in the non-beta-blocker group). The 50 slow flow phenomena comprised 21 TIMI flow grade ≤1 and 29 TIMI flow grade 2. Flow was eventually ameliorated with the use of medications such as nicorandil or nitroglycerin, ballooning, and stenting in all slow flow cases. There were 7 periprocedural myocardial infarctions in 50 slow flow patients (14%). The occurrence of slow flow was not different between the beta-blocker group (29.9%) and the non-beta-blocker group (24.2%; P=.39; Figure 1). The occurrence of slow flow among the types of beta-blockers was also compared (Figure 2). The occurrence of slow flow was not different among the carvedilol group (34.3%), bisoprolol group (25.0%), and other beta-blocker group (31.3%; P=.69). The results of multivariate logistic regression analysis are shown in Table 3. Variables that showed a marginal difference (P<.20) in Tables 1 and 2 were adopted as independent variables. The use of beta-blockers was not significantly associated with slow flow (odds ratio, 0.75; 95% confidence interval, 0.34-1.68; P=.49) after controlling for potential confounding factors.

Since the use of beta-blockers was not found to be a determinant of slow flow, we performed another analysis to try to identify the determinants of slow flow (Table 4). At first, univariate logistic regression analysis was performed using each variable to identify those that were marginally associated with slow flow (P<.20). Next, all variables that showed a marginal association with slow flow in univariate analysis were adopted as independent variables in multivariate logistic regression analysis. Previous myocardial infarction (odds ratio, 3.22; 95% confidence interval, 1.47-7.06; P=.004) and lesion length (5 mm increase) (odds ratio, 1.14; 95% confidence interval, 1.01-1.30; P=.04) were significant determinants of slow flow in this multivariate analysis.

Discussion

Our results from 186 patients receiving RA have shown that there was no significant association between the use of beta-blockers and slow flow during RA. In addition, there was no association between beta-blocker use and slow flow after controlling for potential confounding factors. Our results support the hypothesis that there is no definitive association between slow flow and beta-blocker use in current RA.

Sharma et al reported that slow flow after RA was associated with beta-blocker use, long target lesions, and angina at rest based on multivariate logistic regression analysis.³ There may be several reasons why our results are different from theirs. First, since they did not compare patient characteristics between the beta-blocker and non-beta-blocker groups, their analysis might not have adequately adjusted for confounding factors. Second, there was a substantial difference in RA procedures between their study (August 1994 to August 1995) and our study (January 2008 to April 2011). After RA, 99% of the patients in our study received a stent, whereas only 9%-15% received a stent in their study.¹⁶ In addition, since we were able to implant drug-eluting stents, we could perform RA on more complex lesions such as those in small vessels or diffuse long lesions.^17,18 Therefore, the difference in PCI strategy and PCI indications might have resulted in a higher incidence of slow flow in our study (26.9%) compared with theirs (10%).³ Third, the type of beta-blocker might have been different, although there was no information about the type of beta-blockers in their report.

The mechanism of slow flow during RA is poorly understood. Microvascular dysfunction due to distal embolization of atherosclerotic components such as platelet and fibrin complex, macrophages, and cholesterol crystals may contribute to slow flow.^3,19 One proposed mechanism associated with beta-blocker use is coronary vasospasm.²⁰ Sharma et al speculated that beta-blockade (with unopposed alpha agonism) might contribute to the occurrence of vasospasm during RA.³ Although beta-blockers may contribute to vasospasm in theory, the association between beta-blocker use and vasospasm in the clinical setting is still controversial. Shirotani et al failed to show an association between the use of beta-blockers in patients with acute myocardial infarction and coronary spasm induced by the intracoronary injection of ergonovine.²¹ To date, there is no strong evidence that the use of beta-blockers increases the risk of coronary vasospasm. 

Recently, two prospective randomized studies on slow flow during RA did not include patients that were on beta-blockers at the time of RA.^4,9 Iwasaki et al enrolled a total of 114 patients for RA that were not on beta-blockers at the time of the procedure.⁹ Matsuo et al enrolled a total of 200 patients for RA, and all beta-blockers were discontinued at least 24 hours before the procedure.⁴ The discontinuation of beta-blockers prior to RA would decrease the use of a drug class that has been recommended by the guidelines for coronary artery disease.^10,11 In addition, sudden cessation of beta-blockers may be dangerous due to a possible increase in ischemia.²² Interestingly, there is a possibility that the sudden cessation of beta-blockers may provoke coronary vasospasm.²³ Therefore, discontinuation of beta-blockers in patients undergoing RA should only be done if there is a clearly established clinical benefit.

Our results on the determinants of slow flow should be carefully interpreted. First, the culprit lesion in ACS was not associated with slow flow even in univariate analysis. As described in the Methods section, we do not use RA as initial therapy for culprit lesion in ACS. Therefore, our ACS cases represent a highly selected population. Second, a previous myocardial infarction was significantly associated with slow flow, although no previous studies have identified this association. Reduced cardiac function due to myocardial infarction might affect the occurrence of slow flow. However, chronic heart failure was not associated with slow flow in our study. Further research regarding the association between cardiac function and slow flow may be necessary. Third, the lesion length (5 mm increase) was significantly associated with slow flow in multivariate analysis. Sharma et al also reported that lesion length was associated with slow flow.³ Thus, a diffuse long lesion may be an important determinant of slow flow during RA.

Study limitations. Since this study was designed as a single-center retrospective observational study, there was a risk for patient selection bias and group selection bias. A relatively large number of patients (38) were excluded because of the lack of appropriate angiograms. As we could not perform a statistical power analysis, there is a possibility of beta error. The basis for comparison of our patient cohorts was the manuscript from Sharma et al in the American Journal of Cardiology in 1997.³ Given this historical work was from the mid 1990s, there may be clear differences in treatment strategies and approaches to patients from that era to today that provide an inherent bias in patient selection that cannot be overstated. However, we believe the basic selection of patients for treatment to be relatively similar, and that provides our basis for the comparison.

Conclusion

There is no definitive association between slow flow and the use of beta-blockers during RA in current clinical practice. Discontinuing beta-blockers may not be necessary in patients receiving RA.

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From the Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sakakura and Dr Ako report receiving minor speaking honoraria from Boston Scientific. No other authors report any conflicts regarding the content herein.
Manuscript submitted January 16, 2012, provisional acceptance given March 23, 2012, final version accepted April 9, 2012
Address for correspondence: Kenichi Sakakura, MD, Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Amanuma 1-847, Omiya, Saitama, 330-8503. Email: ZXH03005@nifty.ne.jp