Journal of Atherosclerosis and Thrombosis Vol. 22, No. 5
481
Original Article
Beta-blocker Treatment Does Not Worsen Critical Limb Ischemia in Patients Receiving Endovascular Therapy Yoshimitsu Soga 1, Osamu Iida 2, Mitsuyoshi Takahara 3, Keisuke Hirano 4, Kenji Suzuki 5 and Daizo Kawasaki 6 1
Kokura Memorial Hospital, Department of Cardiology, Kitakyushu, Japan Kansai Rosai Hospital, Cardiovascular center, Amagasaki, Japan 3 Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan 4 Saiseikai Yokohama-city Eastern Hospital, Department of Cardiology, Yokohama, Japan 5 Sendai Kousei Hospital, Department of Cardiology, Sendai, Japan 6 Morinomiya Hospital, Cardiovascular Division, Morinomiya, Japan 2
Aim: It has been reported that beta-blockers (BB) reduce cardiovascular events in patients with atherosclerotic disease. However, little is known about the efficacy of these drugs in patients with critical limb ischemia (CLI). We investigated whether beta-blocker therapy affects the clinical outcomes of CLI patients. Methods: Between March 2004 and December 2011, 1,873 consecutive CLI patients who received endovascular therapy (EVT) (394 BB-treated patients and 1,479 non-BB-treated patients) for de novo infrainguinal lesions were identified retrospectively. A propensity score analysis was used for risk adjustment in a multivariable analysis and one-to-one matching (BB: 305, non-BB 305). The primary endpoint was amputation-free survival (AFS), and the secondary endpoints were overall survival and the rates of limb salvage and freedom from major adverse limb events (MALE; including repeat reintervention, surgical conversion and major amputation). The mean follow-up period was 22±15 months. Results: In the propensity score-matched pair analysis, there were no significant differences in AFS between the patients treated with and without beta-blockers (58.8% vs. 58.5% at three years, logrank p = 0.76). There were also no significant differences in the limb salvage rate (88.3% vs. 88.8 at three years, log-rank P = 0.41), overall survival (63.0% vs. 62.4% at three years, log-rank P = 0.70) and freedom from MALE (43.6% vs. 44.9% at three years, log-rank P = 0.58) between the patients treated with and without beta-blockers. Conclusions: The present results suggest that beta-blocker therapy does not worsen the clinical outcomes after EVT in CLI patients.
See editorial vol. 22: 445-446 J Atheroscler Thromb, 2015; 22: 481-489. Key words: Beta-blocker, Critical limb ischemia, Endovascular therapy
Introduction Beta-blockers are relatively contraindicated for use in patients with peripheral arterial disease (PAD) Address for correspondence: Yoshimitsu Soga, Department of Cardiology, Kokura Memorial Hospital, 1-2-3 Asano, Kokurakita-ku, Kitakyushu, Japan. 802-0001 E-mail: [email protected] Received: July 31, 2014 Accepted for publication: September 16, 2014
due to the risk of symptom aggravation. However, beta-blockers do not exacerbate claudication symptoms 1, 2), and the incidence of ischemic cardiac disease and subsequent cardiovascular events is high in many PAD patients 3, 4). Beta-blockers (BBs) suppress cardiovascular events 5-9) and the potential use of these drugs in patients with PAD is discussed in the Trans-Atlantic Inter-Society consensus Ⅱ (TASCⅡ) guidelines 4). However, it is unclear whether beta-blockers influence both the vital prognosis and prognosis of the lower
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extremities in patients with critical limb ischemia (CLI), for whom outcomes are generally poorer than those observed in claudicant patients. We herein report our results regarding the effects of beta-blockers on clinical outcomes in CLI patients treated with endovascular therapy (EVT). Methods Data Collection and Definitions This study was performed as a multicenter retrospective analysis. Between March 2004 and December 2011, 1,873 consecutive patients (2,255 limbs) with CLI who underwent primary EVT for chronic infrainguinal ischemia were identified retrospectively in a prospectively maintained database and included in the analysis. The mean follow-up period was 22±15 months (range: 1 to 105 months). Baseline demographic and clinical characteristics data were collected from each hospital database. Limb salvage was defined as freedom from major amputation, that is amputation above the ankle. Coronary artery disease (CAD) was defined as stable angina with documented CAD, previous myocardial infarction and/or a history of percutaneous coronary intervention or coronary artery bypass graft surgery. Cerebrovascular disease was defined as a diagnosis of transient ischemic attack or ischemic stroke on a hospital or neurologist report. Heart failure (HF) included a previous diagnosis of HF, history of hospitalization for HF or current treatment for HF. The left ventricular (LV) ejection fraction (EF) was measured using either contrast left ventriculography or echocardiography. Patients with an LVEF of ＜ 40% were regarded as having LV dysfunction. The study protocol was approved by each hospital’s ethics committee and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient. Procedures and Follow-Up All patients were medicated with dual antiplatelet therapy (aspirin 100 mg/day＋clopidogrel 75 mg/ day) before the procedure. Following the insertion of a 4- or 6-Fr sheath via either the crossover approach using a 4- to 6-Fr sheath or antegrade ipsilateral approach using a 4- to 6-Fr sheath, an intra-arterial bolus of 3,000 to 5,000 IU of heparin was injected, with additional heparin given intravenously during the procedure in order to maintain an activated clotting time of ＞ 200 seconds. For SFA lesions, balloon angioplasty was performed with an optimal size after a 0.035-, 0.018- or 0.014-inch guidewire crossed the
lesion. If a suboptimal result caused by flow-limiting dissection or residual stenosis of ＞ 30% was obtained for a femoropopliteal lesion, a stent was implanted and the entire lesion was covered by the stent. Four types of bare-metal nitinol stents were implanted: Luminexx (Bard, Murray Hill, NJ), S.M.A.R.T. (Cordis J&J, Miami, FL), Zilver (Cook Medical, Bloomington, Indiana) and Misago (Terumo, Tokyo Japan). The stent type was determined by the operator, and the stent size was chosen to be 1 to 2 mm larger than the reference vessel diameter. For infrapopliteal lesions, the target lesion was passed with a 0.018- or 0.014-inch guidewire, the diameter and length of the balloon were determined by the operator and the vessel was expanded for at least 60 seconds. If flow-limiting dissection, significant recoil or acute occlusion were noted after balloon angioplasty, the angioplasty technique was performed repeatedly with low pressure and a long inflation time. Bailout stenting was not performed for infrapopliteal lesions. After the procedure, all patients were prescribed lifelong aspirin therapy (100-200 mg/day), with prolonged (at least one month) clopidogrel 75 mg/day and/or cilostazol 100 mg twice a day added at the operator’s discretion. Outcome Measurements The outcome measurements of this study were 30-day mortality, amputation-free survival (AFS), limb salvage, overall survival, freedom from cardiovascular death and freedom from major adverse limb events (MALE; including major amputation, bypass conversion and reintervention). Statistical Analysis The values are reported as the mean±SD. Continuous variables were examined using the unpaired t-test, and categorical variables were compared using the chi-square test. Survival curves were estimated according to the Kaplan-Meier method and compared with the log-rank test. In order to minimize intergroup differences in the baseline characteristics, a propensity score matching analysis was performed. The propensity score was developed using a logistic regression model in which the following variables were entered: age, sex, revascularization date, body mass index, ambulatory status, diabetes mellitus, hypertension, hyperlipidemia, smoking, regular dialysis, cerebrovascular disease, coronary artery disease, LV ejection fraction, Rutherford classification, ankle-brachial index, femoropopliteal revascularization and use of aspirin, thienopyridine, cilostazol, anticoagulant agents or statins. As recommended by Austin 10), we
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matched on the logit of the propensity score within the caliper of 0.2 of the standard deviation of the logit of the propensity score. For a non-inferiority trial with respect to the primary endpoint at three years, the sample size calculations estimated that a total of 223 patients per treatment would be needed for 90% power to detect a 15% difference (0.65 in the non-BB group and 0.50 in the BB group) at the 5% significance level. Assuming that the percentage of dropouts during follow-up after EVT would be approximately 20%, the expected sample size was set to at least 268 patients. Although this study involved non-randomized retrospective data collection, the identification of 305 matched pairs after propensity score matching appeared to be adequate for evaluating the primary endpoint. The outcome measurements were assessed according to the Kaplan-Meier method, and intergroup differences were compared using the log-rank test. The propensity score matching analysis was performed with the R version 2.12.1 software program (R Development Core Team), while the other statistical analyses were performed using the IBM SPSS Statistics Version 19 package (SPSS, Inc.). The consistency of the treatment effect was assessed among nine prespecified subgroups (gender, octogenarians, ambulatory status, HF, LV dysfunction, CAD, diabetes, hemodialysis and tissue loss). The effect in each subgroup was analyzed using a Cox proportional hazards model. A probability value of ＜ 0.05 was considered to be statistically significant in all analyses.
Outcome Measurements In the propensity matched pair analysis, the 30-day mortality rate was significantly lower in the BB group than in the non-BB group (1.0% vs. 3.6%, P = 0.03; Fig. 1). However, the rates of limb loss within 30 days (1.0% vs. 1.6%, P = 0.48) and bypass conversion within 30 days (1.0% vs. 1.0%, P = 0.99) did not differ significantly between the two groups. The 3-year AFS rate was not significantly different between the patients treated with and without beta-blockers (51.8% vs. 55.6%, log-rank P = 0.58; Fig. 2A) and was found to be similar in the two groups in the propensity matching analysis (58.8% vs. 58.5%, log-rank P = 0.76; Fig. 2B). There were also no significant differences in AFS between the patients treated with carvedilol, bisoprolol, atenolol and metoprolol (log-rank P = 0.35). The 3-year limb salvage rate (88.3% vs. 88.8%, log-rank P = 0.41; Fig. 3A), 3-year overall survival rate (63.0% vs. 62.4%, log-rank P = 0.70; Fig. 3B), 3-year freedom from cardiovascular death (76.0% vs. 78.2%, log-rank P = 0.66; Fig. 3C), 3-year freedom from MALE (43.6% vs. 44.9%, log-rank P = 0.58; Fig. 3D), bypass conversion rate (90.6% vs. 94.3%, log-rank P = 0.34) and need for reintervention (45.0% vs. 46.4%, log-rank P = 0.60) did not differ significantly between the beta-blocker and non-beta-blocker groups. A univariate analysis of AFS showed that treatment with beta-blockers did not worsen the outcomes in the prespecified subgroups of patients (Table 2).
Results
Discussion
Baseline Characteristics Applying the inclusion and exclusion criteria, the present cohort included 1,873 CLI patients who underwent primary EVT. After excluding patients with unsuitable matches and matching propensity scores, the analysis included 305 matched pairs (n = 610). The baseline characteristics of these patients are listed in Table 1. The mean age was 72 years, 76% of the subjects had diabetes and 52% were receiving hemodialysis. The indications for treatment with betablockers were HF or LV dysfunction (31%), coronary artery disease (28%), hypertension (28%) and atrial fibrillation (13%). The beta-blockers included carvedilol (63%), bisoprolol (27%), atenolol (8%) and metoprolol (3%). All demographics and clinical characteristics were well balanced in the matched pairs (Table 1).
In this study, we examined the effects of betablockers in CLI patients undergoing EVT. Consequently, the results were similar for the endpoints of AFS, limb salvage, overall survival, CV death and MALE. The outcomes of EVT have recently improved, and this method has become common as a result of technical developments and improvements in devices 11-13). Providing general anesthesia is difficult in many CLI patients with severe CAD, HF or LV dysfunction, although the number of high-risk patients who receive EVT is likely to increase. Beta-blocker therapy may be effective in such patients 5-9), and the results of the current study indicate that there is no reason not to use these drugs in CLI patients judged to require beta-blockers. Beta-blockers may improve the prognosis during the perioperative period for vascular surgery 14, 15), and the TASCⅡ guidelines suggest that beta-adrenergic blockers should be given perioperatively in patients
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Table 1. Patient characteristics
Age (yrs) ＞ 80 yrs (%) Female (%) Body Mass Index (kg/m 2) ＜ 18 (%) ＞ 25 (%) Ambulatory (%) Hypertension (%) Dyslipidemia (%) Diabetes (%) Hemodialysis (%) Current Smoker (%) COPD (%) Cerebrovascular Disease (%) Coronary Artery Disease (%) Heart failure (%) LV dysfunction (%) Rutherford class Ⅳ/Ⅴ/Ⅵ Tissue loss (%) Medication Aspirin (%) Thienopyridines (%) Cilostazol (%) Statins (%) Anti-coagulant (%) Details of beta-blockers Carvedilol (%) Bisoprolol (%) Atenolol (%) Metoprolol (%)
Beta-blocker (−) N = 305
Beta-blocker (＋) N = 305
p-value
72±11 74 (24) 106 (35) 22±4 42 (14) 57 (19) 185 (61) 252 (83) 146 (48) 232 (76) 159 (52) 68 (22) 10 (3) 88 (29) 182 (60) 105 (34) 51 (17)
73±9 63 (21) 107 (35) 22±3 35 (11) 47 (15) 176 (58) 251 (82) 148 (49) 231 (76) 161 (53) 65 (21) 12 (4) 93 (30) 184 (60) 114 (37) 60 (20)
0.49 0.29 0.93 0.83 0.39 0.28 0.46 0.92 0.87 0.92 0.87 0.77 0.66 0.67 0.87 0.45 0.34
76/176/53 229 (75)
92/155/58 213 (70)
0.21 0.15
262 (86) 121 (40) 141 (46) 105 (34) 68 (22)
257 (84) 135 (44) 135 (44) 114 (37) 58 (19)
0.57 0.25 0.63 0.45 0.32
191 (63) 83 (27) 23 (8) 8 (3)
COPD: Chronic Obstructive Pulmonary Disease, LV: left ventricle, LV dysfunction was defined as a LV ejection fraction of ＜ 40%
＊
Fig. 1. 30-day mortality
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A: Before propensity-match
B: After propensity-match 100 Amputation-free survival (%)
Amputation-free survival (%)
100 80 60 40 Logrank P = 0.58 Beta-blocker (+) (N=394) Beta-blocker ( - ) (N=1479)
20
80 60 40 Logrank P = 0.76 Beta-blocker (+) (N=305) Beta-blocker ( - ) (N=305)
20 0
0 0
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No. at Risk 394 %
100
No. at Risk 1479 %
100
1Y
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220
107
47
74.6
61.6
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845
492
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73.2
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178
82
34
75.5
62.6
58.8
178
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75.8
62.5
58.5
Fig. 2. Amputation-free survival
with PAD undergoing vascular surgery in order to decrease cardiac morbidity and mortality 4). In the present study, the 30-day mortality rate was significantly decreased among those treated with beta-blockers, without a corresponding increase in major amputation or bypass conversion within 30 days after surgery. The perioperative prognosis of CLI patients with cardiac failure is poor 16), and the use of beta-blockers may be required in high-risk cases. Beta-blocker therapy may also be useful for treating diseases such as LV dysfunction and HF 5-7), as improved prognoses after beta-blocker administration have been reported in such patients. However, the improvements in the perioperative prognosis may be due to reductions in heart rate, rather than the effects of beta-blocker treatment 14, 15). Therefore, heart rate monitoring after perioperative beta-blocker administration is important in CLI patients. In order to evaluate the efficacy of beta-blockers, we examined the rates of HF, LV dysfunction and CAD, each of which are indications for BB therapy, in groups based on AFS using data obtained prior to propensity matching. Notably, there were significant decreases in HF (HR 1.6, 95%CI 1.3-1.9, p ＜ 0.0001), LV dysfunction (HR 2.0, 95%CI 1.7-2.5, p ＜ 0.0001) and CAD (HR 1.2, 95%CI 1.1-1.4, p = 0.006). Since AFS is determined based on the rates
of limb salvage and overall survival, each of these parameters were also examined. For limb salvage, there were no significant differences in HF (HR 1.3, 95%CI 0.9-1.8, p = 0.19) or CAD (HR 1.1, 95%CI 0.8-1.5, p = 0.41), although a significant decrease was noted in LV dysfunction (HR 1.7, 95%CI 1.1-2.5, p = 0.01). For overall survival, there were significant decreases in HF (HR 1.7, 95%CI 1.4-2.1, p ＜ 0.0001), LV dysfunction (HR 2.4, 95%CI 1.8-3.2, p ＜ 0.0001) and CAD (HR 1.5, 95%CI 1.2-1.9, p = 0.0006). For CV death only, these difference were even clearer for HF (HR 2.1, 95%CI 1.6-2.7, p ＜ 0.0001), LV dysfunction (HR 2.2, 95%CI 1.8-2.7, p ＜ 0.0001) and CAD (HR 1.3, 95%CI 1.1-1.5, p = 0.002). Meanwhile, HF (HR 1.3, 95%CI 1.1-1.6, p = 0.007), LV dysfunction (HR 1.7, 95%CI 1.4-2.1, p ＜ 0.0001) and CAD (HR 1.3, 95%CI 1.1-1.5, p = 0.002) were found to be significantly associated with the incidence of MALE. These data suggest that HF, LV dysfunction and CAD, for which beta-blockers were indicated in this study, are closely correlated with the outcomes based on AFS, overall survival (especially CV death) and MALE in CLI patients, with LV dysfunction being a particularly reliable predictor. HF and LV dysfunction result in decreased patency in the chronic phase 17), and the incidence of
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A: Limb salvage rate
B: Overall survival 100
Overall survival (%)
Limb salvage rate (%)
100 80 60 Logrank P = 0.41 40 Beta-blocker (+) (N=305) Beta-blocker ( - ) (N=305)
20
80 60 Logrank P = 0.70 40 Beta-blocker (+) (N=305) Beta-blocker ( - ) (N=305)
20 0
0 0
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1Y
No. at Risk 305 %
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%
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82
33
92.2
91.7
88.3
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79
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90.4
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C: Freedom from CV death
0 Beta-blocker (+) Beta-blocker (-)
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No. at Risk 305 %
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86
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79.6
66.0
63.0
193
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82.0
67.8
62.4
D: Freedom from MALE 100 Freedom from MALE (%)
100 Freedom from CV death (%)
3
Time after procedure (yrs)
Time after procedure (yrs)
0
2
80 60 Logrank P = 0.66 40 Beta-blocker (+) (N=305) Beta-blocker ( - ) (N=305)
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80 60 Logrank P = 0.58
40
Beta-blocker (+) (N=305) Beta-blocker ( - ) (N=305)
20 0
0 0
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0 Beta-blocker (+) Beta-blocker (-)
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86
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78.5
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No. at Risk 305
193
88
41
89.3
80.6
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% %
Fig. 3. Event-free survival
100
2
3
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187
No. at Risk 305
1
0 Beta-blocker (+) Beta-blocker (-)
1Y
2Y
3Y
123
49
18
100
62.9
54.8
43.6
No. at Risk 305
115
41
17
60.0
51.6
44.9
No. at Risk 305 % %
100
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Table 2. Univariate subgroup analysis of amputation-free survival in the patients treated with and without betablockers Group All Patients Male female Age ≧ 80 yrs Age ＜ 80 yrs Ambulatory (＋) Ambulatory (−) Heart failure (＋) Heart failure (−) LV dysfunction (＋) LV dysfunction (−) CAD (＋) CAD (−) Diabetes (＋) Diabetes (−) Hemodialysis (＋) Hemodialysis (−) Rest pain Tissue loss Rutherford class Ⅴ Rutherford class Ⅵ
No. of Pts (AFS)
HR
p-value
95%CI
610 (203) 397 (139) 213 (64) 137 (46) 473 (157) 361 (85) 249 (118) 219 (87) 391 (116) 111 (63) 499 (140) 366 (129) 244 (74) 463 (151) 147 (52) 320 (139) 290 (64) 168 (36) 442 (167) 331 (111) 111 (56)
0.96 0.92 1.04 1.21 0.89 1.03 0.86 0.97 0.91 0.94 0.94 0.94 0.99 1.05 0.72 0.92 1.03 1.03 0.99 1.08 0.71
0.76 0.62 0.87 0.52 0.47 0.91 0.40 0.90 0.60 0.81 0.73 0.73 0.97 0.76 0.25 0.64 0.90 0.92 0.96 0.67 0.21
0.73-1.26 0.67-1.29 0.64-1.71 0.68-2.16 0.65-1.22 0.67-1.57 0.60-1.23 0.63-1.50 0.63-1.31 0.57-1.55 0.68-1.32 0.67 - 1.33 0.63-1.57 0.76-1.45 0.42-1.26 0.66-1.29 0.63-1.68 0.53-2.02 0.73-1.35 0.75-1.57 0.42-1.20
P int
0.90 0.30 0.41 0.31 0.63 0.54 0.31 0.72 0.77 0.20
HR: hazard ratio, CI: confidence interval, CAD: coronary artery disease
MALE is likely to be high in patients with these conditions. Indeed, the incidence of MALE was high in the current study, as mentioned above. For diseases such as HF, LV dysfunction and CAD that influence the outcomes of CLI patients, treatment with betablockers decreases the frequency of hospitalization for cardiac failure and improves the prognosis 5-9). Similar effects were expected in our study; however, a subgroup analysis of AFS showed no clear effects of betablockers in any group (Table 2). This may be due to the fact that the inhibitory effects of beta-blockers on cardiovascular events were noted primarily in the patients with a certain vital prognosis. In particular, the CLI patients with a 3-year survival rate of 63% in our study had an extremely poor prognosis, and thus their survival period may have been insufficient to demonstrate any inhibitory effects of beta-blockers on cardiovascular events. In addition, the causes of death in 178 patients who died during the observation period among the 610 patients included in the propensity matched pairs analysis included 97 (54%) cardiovscular deaths (including sudden death) and 66 (37%) non-cardiovascular deaths. Moreover, many patients with non-cardiovascular death had infections, such as sepsis and pneumonia. Infection is included in the cause of death in ≥ 25% of CLI patients 18), and
improving the prognosis of CLI may be difficult without sufficiently controlling infection, even if betablockers are effective in preventing cardiovascular events. The TASCⅡ guidelines 4) suggest that beta-blockers should be used in cases of PAD in order to decrease cardiac morbidity and mortality, although it is unclear which beta-blockers are most appropriate for PAD or CLI patients. Carvedilol and bisoprolol were generally used in this study, as high protective effects on the heart have been reported for drugs with b1 selectivity or a-blocking activity 5, 7, 19), lipid-soluble agents 20) and medications with no intrinsic sympathomimetic activity 21) in large-scale clinical studies. In addition, the use of long-acting drugs is desirable from the standpoint of internal medicine compliance, and this is one reason for the common daily clinical use of carvedilol and bisoprolol. Further examinations of the appropriate type and dose of beta-blockers are required, with monitoring of the heart rate and blood pressure as markers of treatment outcomes. Limitations There are several limitations associated with this study. First, the study design was retrospective, despite
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the use of a large-scale prospective database and propensity-matched scores, and there was considerable bias in many of the data assignments. Therefore, a prospective randomized investigation is needed to verify our findings. Second, the current results showed that treatment with beta-blockers did not affect the clinical outcomes of the patients. However, it is unclear if each specific beta-blocker had no effect compared to that observed in the patients treated without beta-blocker therapy, as the number of patients who received each drug was too small to conduct an analysis. Finally, the dose-dependent effects of beta-blockers were not investigated. Hence, further research of the dose is needed to clarify our findings. Although the preventive effects of beta-blockers on cardiac disease are clear based on widespread evidence of cardioprotection, the efficacy of beta-blockers in cases of CLI is uncertain, despite the fact that CLI causes life-threatening cardiac diseases and infections. Within the above limitations, the results of the current study indicate that beta-blockers have beneficial clinical effects in cases of CLI and are suitable for daily treatment in these patients. Conclusion The present findings suggest that the use of betablockers does not adversely affect the rates of AFS, limb salvage, all-cause mortality or MALE after EVT in patients with CLI. Taking into account contraindications, beta-blockers may be administered in patients judged to require this treatment, without worsening the clinical outcomes. Financial Support None. Conflicts of Interest None declared. References 1) Paravastu SC, Mendonca DA, da Silva A: Beta blockers for peripheral arterial disease. Eur J Vasc Endovasc Surg, 2009; 38: 66-70 2) Radack K, Deck C: Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med, 1991; 151: 1769-1776 3) Steg PG, Bhatt DL, Wilson PW, D’Agostino R Sr, Ohman EM, Röther J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto S; REACH Registry Investiga-
tors: One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA, 2007; 297: 1197-1206 4) Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al.: Inter-Society consensus for the management of peripheral arterial disease (TASC Ⅱ). Eur J Vasc Endovasc Surg, 2007; 33 (Suppl 1): S1-S75 5) CIBIS-Ⅱ investigators and Committee: The cardiac insufficiency bisoprolol study Ⅱ (CIBIS-Ⅱ): a randomized trial. Lancet, 1999; 353: 9-13 6) MERIT-HF Study Group: Effect of metoprolol CRXL in chronic heart failure: Metoprolol CRXL Randomized Investigation Trial in Congestive Heart Failure (MERITHF). Lancet, 1999; 353: 2001-2007 7) Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival Study Group: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med, 2001; 344: 1651-1658 8) The CAPRICORN investigators: Effect of carvedilol on outcome after myocardial infarction in patients with leftventricular dysfunction; the CAPRICORN randomized trial. Lancet, 2001; 357: 1385-1390 9) Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, Daly C, De Backer G, Hjemdahl P, Lopez-Sendon J, Marco J, Morais J, Pepper J, Sechtem U, Simoons M, Thygesen K, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deckers J, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo J, Zamorano JL; Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology; ESC Committee for Practice Guidelines (CPG): Guidelines on the management of stable angina pectoris: exective summary. The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J, 2006; 27: 1341-1381 10) Austin PC: Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat, 2011; 10: 150-161 11) Anderson PL, Gelijns A, Moskowitz A, Arons R, Gupta L, Weinberg A, Faries PL, Nowygrod R, Kent KC: Understanding trends in inpatient surgical volume: vascular interventions, 1980-2000. J Vasc Surg, 2004; 39: 12001208 12) Goodney PP, Beck AW, Nagle J, Welch HG, Zwolak RM: National trends in lower extremity bypass surgery, endovascular interventions, and major amputations. J Vasc Surg, 2009; 50: 54-60 13) Rowe VL, Lee W, Weaver FA, Etzioni D: Patterns of treatment for peripheral arterial disease in the United States: 1996-2005. J Vasc Surg, 2009; 49: 910-917 14) Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, Baars HF, Yo TI, Trocino G, Vigna C, Roelandt JR, van Urk H: The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med, 1999; 341: 1789-1794
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15) Flu WJ, van Kuijk JP, Chonchol M, Winkel TA, Verhagen HJ, Bax JJ, Poldermans D: Timing of pre-operative Betablocker treatment in vascular surgery patients: influence on post-operative outcome. J Am Coll Cardiol, 2010; 56: 1922-1929 16) Vogel TR, Dombrovskiy VY, Carson JL, Graham AM: Inhospital and 30-day outcomes after tibioperoneal interventions in the US Medicare population with critical limb ischemia. J Vasc Surg, 2011; 54: 109-115 17) Meltzer AJ, Shrikhande G, Gallagher KA, Aiello FA, Kahn S, Connolly P, McKinsey JF: Heart failure is associated with reduced patency after endovascular intervention for symptomatic peripheral arterial disease. J Vasc Surg, 2012; 55: 353-362 18) Soga Y, Iida O, Hirano K, Yokoi H, Nanto S, Nobuyoshi
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M: Mid-term clinical outcome and predictors of vessel patency after femoropopliteal stenting with self-expandable nitinol stent. J Vasc Surg, 2010; 52: 608-615 19) CIBIS Investigators and Committees: A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation, 1994; 9: 17651773 20) Carlberg B, Samuelsson O, Lindholm LH: Atenolol in hypertension: is it a wise choice? Lancet, 2004 6-12; 364: 1684-1689 21) Freemantle N, Cleland J, Young P, Mason J, Harrison J: beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ, 1999; 318: 1730-1737
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Original Article
Beta-blocker Treatment Does Not Worsen Critical Limb Ischemia in Patients Receiving Endovascular Therapy Yoshimitsu Soga 1, Osamu Iida 2, Mitsuyoshi Takahara 3, Keisuke Hirano 4, Kenji Suzuki 5 and Daizo Kawasaki 6 1
Kokura Memorial Hospital, Department of Cardiology, Kitakyushu, Japan Kansai Rosai Hospital, Cardiovascular center, Amagasaki, Japan 3 Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan 4 Saiseikai Yokohama-city Eastern Hospital, Department of Cardiology, Yokohama, Japan 5 Sendai Kousei Hospital, Department of Cardiology, Sendai, Japan 6 Morinomiya Hospital, Cardiovascular Division, Morinomiya, Japan 2
Aim: It has been reported that beta-blockers (BB) reduce cardiovascular events in patients with atherosclerotic disease. However, little is known about the efficacy of these drugs in patients with critical limb ischemia (CLI). We investigated whether beta-blocker therapy affects the clinical outcomes of CLI patients. Methods: Between March 2004 and December 2011, 1,873 consecutive CLI patients who received endovascular therapy (EVT) (394 BB-treated patients and 1,479 non-BB-treated patients) for de novo infrainguinal lesions were identified retrospectively. A propensity score analysis was used for risk adjustment in a multivariable analysis and one-to-one matching (BB: 305, non-BB 305). The primary endpoint was amputation-free survival (AFS), and the secondary endpoints were overall survival and the rates of limb salvage and freedom from major adverse limb events (MALE; including repeat reintervention, surgical conversion and major amputation). The mean follow-up period was 22±15 months. Results: In the propensity score-matched pair analysis, there were no significant differences in AFS between the patients treated with and without beta-blockers (58.8% vs. 58.5% at three years, logrank p = 0.76). There were also no significant differences in the limb salvage rate (88.3% vs. 88.8 at three years, log-rank P = 0.41), overall survival (63.0% vs. 62.4% at three years, log-rank P = 0.70) and freedom from MALE (43.6% vs. 44.9% at three years, log-rank P = 0.58) between the patients treated with and without beta-blockers. Conclusions: The present results suggest that beta-blocker therapy does not worsen the clinical outcomes after EVT in CLI patients.
See editorial vol. 22: 445-446 J Atheroscler Thromb, 2015; 22: 481-489. Key words: Beta-blocker, Critical limb ischemia, Endovascular therapy
Introduction Beta-blockers are relatively contraindicated for use in patients with peripheral arterial disease (PAD) Address for correspondence: Yoshimitsu Soga, Department of Cardiology, Kokura Memorial Hospital, 1-2-3 Asano, Kokurakita-ku, Kitakyushu, Japan. 802-0001 E-mail: [email protected] Received: July 31, 2014 Accepted for publication: September 16, 2014
due to the risk of symptom aggravation. However, beta-blockers do not exacerbate claudication symptoms 1, 2), and the incidence of ischemic cardiac disease and subsequent cardiovascular events is high in many PAD patients 3, 4). Beta-blockers (BBs) suppress cardiovascular events 5-9) and the potential use of these drugs in patients with PAD is discussed in the Trans-Atlantic Inter-Society consensus Ⅱ (TASCⅡ) guidelines 4). However, it is unclear whether beta-blockers influence both the vital prognosis and prognosis of the lower
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extremities in patients with critical limb ischemia (CLI), for whom outcomes are generally poorer than those observed in claudicant patients. We herein report our results regarding the effects of beta-blockers on clinical outcomes in CLI patients treated with endovascular therapy (EVT). Methods Data Collection and Definitions This study was performed as a multicenter retrospective analysis. Between March 2004 and December 2011, 1,873 consecutive patients (2,255 limbs) with CLI who underwent primary EVT for chronic infrainguinal ischemia were identified retrospectively in a prospectively maintained database and included in the analysis. The mean follow-up period was 22±15 months (range: 1 to 105 months). Baseline demographic and clinical characteristics data were collected from each hospital database. Limb salvage was defined as freedom from major amputation, that is amputation above the ankle. Coronary artery disease (CAD) was defined as stable angina with documented CAD, previous myocardial infarction and/or a history of percutaneous coronary intervention or coronary artery bypass graft surgery. Cerebrovascular disease was defined as a diagnosis of transient ischemic attack or ischemic stroke on a hospital or neurologist report. Heart failure (HF) included a previous diagnosis of HF, history of hospitalization for HF or current treatment for HF. The left ventricular (LV) ejection fraction (EF) was measured using either contrast left ventriculography or echocardiography. Patients with an LVEF of ＜ 40% were regarded as having LV dysfunction. The study protocol was approved by each hospital’s ethics committee and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient. Procedures and Follow-Up All patients were medicated with dual antiplatelet therapy (aspirin 100 mg/day＋clopidogrel 75 mg/ day) before the procedure. Following the insertion of a 4- or 6-Fr sheath via either the crossover approach using a 4- to 6-Fr sheath or antegrade ipsilateral approach using a 4- to 6-Fr sheath, an intra-arterial bolus of 3,000 to 5,000 IU of heparin was injected, with additional heparin given intravenously during the procedure in order to maintain an activated clotting time of ＞ 200 seconds. For SFA lesions, balloon angioplasty was performed with an optimal size after a 0.035-, 0.018- or 0.014-inch guidewire crossed the
lesion. If a suboptimal result caused by flow-limiting dissection or residual stenosis of ＞ 30% was obtained for a femoropopliteal lesion, a stent was implanted and the entire lesion was covered by the stent. Four types of bare-metal nitinol stents were implanted: Luminexx (Bard, Murray Hill, NJ), S.M.A.R.T. (Cordis J&J, Miami, FL), Zilver (Cook Medical, Bloomington, Indiana) and Misago (Terumo, Tokyo Japan). The stent type was determined by the operator, and the stent size was chosen to be 1 to 2 mm larger than the reference vessel diameter. For infrapopliteal lesions, the target lesion was passed with a 0.018- or 0.014-inch guidewire, the diameter and length of the balloon were determined by the operator and the vessel was expanded for at least 60 seconds. If flow-limiting dissection, significant recoil or acute occlusion were noted after balloon angioplasty, the angioplasty technique was performed repeatedly with low pressure and a long inflation time. Bailout stenting was not performed for infrapopliteal lesions. After the procedure, all patients were prescribed lifelong aspirin therapy (100-200 mg/day), with prolonged (at least one month) clopidogrel 75 mg/day and/or cilostazol 100 mg twice a day added at the operator’s discretion. Outcome Measurements The outcome measurements of this study were 30-day mortality, amputation-free survival (AFS), limb salvage, overall survival, freedom from cardiovascular death and freedom from major adverse limb events (MALE; including major amputation, bypass conversion and reintervention). Statistical Analysis The values are reported as the mean±SD. Continuous variables were examined using the unpaired t-test, and categorical variables were compared using the chi-square test. Survival curves were estimated according to the Kaplan-Meier method and compared with the log-rank test. In order to minimize intergroup differences in the baseline characteristics, a propensity score matching analysis was performed. The propensity score was developed using a logistic regression model in which the following variables were entered: age, sex, revascularization date, body mass index, ambulatory status, diabetes mellitus, hypertension, hyperlipidemia, smoking, regular dialysis, cerebrovascular disease, coronary artery disease, LV ejection fraction, Rutherford classification, ankle-brachial index, femoropopliteal revascularization and use of aspirin, thienopyridine, cilostazol, anticoagulant agents or statins. As recommended by Austin 10), we
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matched on the logit of the propensity score within the caliper of 0.2 of the standard deviation of the logit of the propensity score. For a non-inferiority trial with respect to the primary endpoint at three years, the sample size calculations estimated that a total of 223 patients per treatment would be needed for 90% power to detect a 15% difference (0.65 in the non-BB group and 0.50 in the BB group) at the 5% significance level. Assuming that the percentage of dropouts during follow-up after EVT would be approximately 20%, the expected sample size was set to at least 268 patients. Although this study involved non-randomized retrospective data collection, the identification of 305 matched pairs after propensity score matching appeared to be adequate for evaluating the primary endpoint. The outcome measurements were assessed according to the Kaplan-Meier method, and intergroup differences were compared using the log-rank test. The propensity score matching analysis was performed with the R version 2.12.1 software program (R Development Core Team), while the other statistical analyses were performed using the IBM SPSS Statistics Version 19 package (SPSS, Inc.). The consistency of the treatment effect was assessed among nine prespecified subgroups (gender, octogenarians, ambulatory status, HF, LV dysfunction, CAD, diabetes, hemodialysis and tissue loss). The effect in each subgroup was analyzed using a Cox proportional hazards model. A probability value of ＜ 0.05 was considered to be statistically significant in all analyses.
Outcome Measurements In the propensity matched pair analysis, the 30-day mortality rate was significantly lower in the BB group than in the non-BB group (1.0% vs. 3.6%, P = 0.03; Fig. 1). However, the rates of limb loss within 30 days (1.0% vs. 1.6%, P = 0.48) and bypass conversion within 30 days (1.0% vs. 1.0%, P = 0.99) did not differ significantly between the two groups. The 3-year AFS rate was not significantly different between the patients treated with and without beta-blockers (51.8% vs. 55.6%, log-rank P = 0.58; Fig. 2A) and was found to be similar in the two groups in the propensity matching analysis (58.8% vs. 58.5%, log-rank P = 0.76; Fig. 2B). There were also no significant differences in AFS between the patients treated with carvedilol, bisoprolol, atenolol and metoprolol (log-rank P = 0.35). The 3-year limb salvage rate (88.3% vs. 88.8%, log-rank P = 0.41; Fig. 3A), 3-year overall survival rate (63.0% vs. 62.4%, log-rank P = 0.70; Fig. 3B), 3-year freedom from cardiovascular death (76.0% vs. 78.2%, log-rank P = 0.66; Fig. 3C), 3-year freedom from MALE (43.6% vs. 44.9%, log-rank P = 0.58; Fig. 3D), bypass conversion rate (90.6% vs. 94.3%, log-rank P = 0.34) and need for reintervention (45.0% vs. 46.4%, log-rank P = 0.60) did not differ significantly between the beta-blocker and non-beta-blocker groups. A univariate analysis of AFS showed that treatment with beta-blockers did not worsen the outcomes in the prespecified subgroups of patients (Table 2).
Results
Discussion
Baseline Characteristics Applying the inclusion and exclusion criteria, the present cohort included 1,873 CLI patients who underwent primary EVT. After excluding patients with unsuitable matches and matching propensity scores, the analysis included 305 matched pairs (n = 610). The baseline characteristics of these patients are listed in Table 1. The mean age was 72 years, 76% of the subjects had diabetes and 52% were receiving hemodialysis. The indications for treatment with betablockers were HF or LV dysfunction (31%), coronary artery disease (28%), hypertension (28%) and atrial fibrillation (13%). The beta-blockers included carvedilol (63%), bisoprolol (27%), atenolol (8%) and metoprolol (3%). All demographics and clinical characteristics were well balanced in the matched pairs (Table 1).
In this study, we examined the effects of betablockers in CLI patients undergoing EVT. Consequently, the results were similar for the endpoints of AFS, limb salvage, overall survival, CV death and MALE. The outcomes of EVT have recently improved, and this method has become common as a result of technical developments and improvements in devices 11-13). Providing general anesthesia is difficult in many CLI patients with severe CAD, HF or LV dysfunction, although the number of high-risk patients who receive EVT is likely to increase. Beta-blocker therapy may be effective in such patients 5-9), and the results of the current study indicate that there is no reason not to use these drugs in CLI patients judged to require beta-blockers. Beta-blockers may improve the prognosis during the perioperative period for vascular surgery 14, 15), and the TASCⅡ guidelines suggest that beta-adrenergic blockers should be given perioperatively in patients
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Table 1. Patient characteristics
Age (yrs) ＞ 80 yrs (%) Female (%) Body Mass Index (kg/m 2) ＜ 18 (%) ＞ 25 (%) Ambulatory (%) Hypertension (%) Dyslipidemia (%) Diabetes (%) Hemodialysis (%) Current Smoker (%) COPD (%) Cerebrovascular Disease (%) Coronary Artery Disease (%) Heart failure (%) LV dysfunction (%) Rutherford class Ⅳ/Ⅴ/Ⅵ Tissue loss (%) Medication Aspirin (%) Thienopyridines (%) Cilostazol (%) Statins (%) Anti-coagulant (%) Details of beta-blockers Carvedilol (%) Bisoprolol (%) Atenolol (%) Metoprolol (%)
Beta-blocker (−) N = 305
Beta-blocker (＋) N = 305
p-value
72±11 74 (24) 106 (35) 22±4 42 (14) 57 (19) 185 (61) 252 (83) 146 (48) 232 (76) 159 (52) 68 (22) 10 (3) 88 (29) 182 (60) 105 (34) 51 (17)
73±9 63 (21) 107 (35) 22±3 35 (11) 47 (15) 176 (58) 251 (82) 148 (49) 231 (76) 161 (53) 65 (21) 12 (4) 93 (30) 184 (60) 114 (37) 60 (20)
0.49 0.29 0.93 0.83 0.39 0.28 0.46 0.92 0.87 0.92 0.87 0.77 0.66 0.67 0.87 0.45 0.34
76/176/53 229 (75)
92/155/58 213 (70)
0.21 0.15
262 (86) 121 (40) 141 (46) 105 (34) 68 (22)
257 (84) 135 (44) 135 (44) 114 (37) 58 (19)
0.57 0.25 0.63 0.45 0.32
191 (63) 83 (27) 23 (8) 8 (3)
COPD: Chronic Obstructive Pulmonary Disease, LV: left ventricle, LV dysfunction was defined as a LV ejection fraction of ＜ 40%
＊
Fig. 1. 30-day mortality
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A: Before propensity-match
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100 80 60 40 Logrank P = 0.58 Beta-blocker (+) (N=394) Beta-blocker ( - ) (N=1479)
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with PAD undergoing vascular surgery in order to decrease cardiac morbidity and mortality 4). In the present study, the 30-day mortality rate was significantly decreased among those treated with beta-blockers, without a corresponding increase in major amputation or bypass conversion within 30 days after surgery. The perioperative prognosis of CLI patients with cardiac failure is poor 16), and the use of beta-blockers may be required in high-risk cases. Beta-blocker therapy may also be useful for treating diseases such as LV dysfunction and HF 5-7), as improved prognoses after beta-blocker administration have been reported in such patients. However, the improvements in the perioperative prognosis may be due to reductions in heart rate, rather than the effects of beta-blocker treatment 14, 15). Therefore, heart rate monitoring after perioperative beta-blocker administration is important in CLI patients. In order to evaluate the efficacy of beta-blockers, we examined the rates of HF, LV dysfunction and CAD, each of which are indications for BB therapy, in groups based on AFS using data obtained prior to propensity matching. Notably, there were significant decreases in HF (HR 1.6, 95%CI 1.3-1.9, p ＜ 0.0001), LV dysfunction (HR 2.0, 95%CI 1.7-2.5, p ＜ 0.0001) and CAD (HR 1.2, 95%CI 1.1-1.4, p = 0.006). Since AFS is determined based on the rates
of limb salvage and overall survival, each of these parameters were also examined. For limb salvage, there were no significant differences in HF (HR 1.3, 95%CI 0.9-1.8, p = 0.19) or CAD (HR 1.1, 95%CI 0.8-1.5, p = 0.41), although a significant decrease was noted in LV dysfunction (HR 1.7, 95%CI 1.1-2.5, p = 0.01). For overall survival, there were significant decreases in HF (HR 1.7, 95%CI 1.4-2.1, p ＜ 0.0001), LV dysfunction (HR 2.4, 95%CI 1.8-3.2, p ＜ 0.0001) and CAD (HR 1.5, 95%CI 1.2-1.9, p = 0.0006). For CV death only, these difference were even clearer for HF (HR 2.1, 95%CI 1.6-2.7, p ＜ 0.0001), LV dysfunction (HR 2.2, 95%CI 1.8-2.7, p ＜ 0.0001) and CAD (HR 1.3, 95%CI 1.1-1.5, p = 0.002). Meanwhile, HF (HR 1.3, 95%CI 1.1-1.6, p = 0.007), LV dysfunction (HR 1.7, 95%CI 1.4-2.1, p ＜ 0.0001) and CAD (HR 1.3, 95%CI 1.1-1.5, p = 0.002) were found to be significantly associated with the incidence of MALE. These data suggest that HF, LV dysfunction and CAD, for which beta-blockers were indicated in this study, are closely correlated with the outcomes based on AFS, overall survival (especially CV death) and MALE in CLI patients, with LV dysfunction being a particularly reliable predictor. HF and LV dysfunction result in decreased patency in the chronic phase 17), and the incidence of
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A: Limb salvage rate
B: Overall survival 100
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100 80 60 Logrank P = 0.41 40 Beta-blocker (+) (N=305) Beta-blocker ( - ) (N=305)
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Table 2. Univariate subgroup analysis of amputation-free survival in the patients treated with and without betablockers Group All Patients Male female Age ≧ 80 yrs Age ＜ 80 yrs Ambulatory (＋) Ambulatory (−) Heart failure (＋) Heart failure (−) LV dysfunction (＋) LV dysfunction (−) CAD (＋) CAD (−) Diabetes (＋) Diabetes (−) Hemodialysis (＋) Hemodialysis (−) Rest pain Tissue loss Rutherford class Ⅴ Rutherford class Ⅵ
No. of Pts (AFS)
HR
p-value
95%CI
610 (203) 397 (139) 213 (64) 137 (46) 473 (157) 361 (85) 249 (118) 219 (87) 391 (116) 111 (63) 499 (140) 366 (129) 244 (74) 463 (151) 147 (52) 320 (139) 290 (64) 168 (36) 442 (167) 331 (111) 111 (56)
0.96 0.92 1.04 1.21 0.89 1.03 0.86 0.97 0.91 0.94 0.94 0.94 0.99 1.05 0.72 0.92 1.03 1.03 0.99 1.08 0.71
0.76 0.62 0.87 0.52 0.47 0.91 0.40 0.90 0.60 0.81 0.73 0.73 0.97 0.76 0.25 0.64 0.90 0.92 0.96 0.67 0.21
0.73-1.26 0.67-1.29 0.64-1.71 0.68-2.16 0.65-1.22 0.67-1.57 0.60-1.23 0.63-1.50 0.63-1.31 0.57-1.55 0.68-1.32 0.67 - 1.33 0.63-1.57 0.76-1.45 0.42-1.26 0.66-1.29 0.63-1.68 0.53-2.02 0.73-1.35 0.75-1.57 0.42-1.20
P int
0.90 0.30 0.41 0.31 0.63 0.54 0.31 0.72 0.77 0.20
HR: hazard ratio, CI: confidence interval, CAD: coronary artery disease
MALE is likely to be high in patients with these conditions. Indeed, the incidence of MALE was high in the current study, as mentioned above. For diseases such as HF, LV dysfunction and CAD that influence the outcomes of CLI patients, treatment with betablockers decreases the frequency of hospitalization for cardiac failure and improves the prognosis 5-9). Similar effects were expected in our study; however, a subgroup analysis of AFS showed no clear effects of betablockers in any group (Table 2). This may be due to the fact that the inhibitory effects of beta-blockers on cardiovascular events were noted primarily in the patients with a certain vital prognosis. In particular, the CLI patients with a 3-year survival rate of 63% in our study had an extremely poor prognosis, and thus their survival period may have been insufficient to demonstrate any inhibitory effects of beta-blockers on cardiovascular events. In addition, the causes of death in 178 patients who died during the observation period among the 610 patients included in the propensity matched pairs analysis included 97 (54%) cardiovscular deaths (including sudden death) and 66 (37%) non-cardiovascular deaths. Moreover, many patients with non-cardiovascular death had infections, such as sepsis and pneumonia. Infection is included in the cause of death in ≥ 25% of CLI patients 18), and
improving the prognosis of CLI may be difficult without sufficiently controlling infection, even if betablockers are effective in preventing cardiovascular events. The TASCⅡ guidelines 4) suggest that beta-blockers should be used in cases of PAD in order to decrease cardiac morbidity and mortality, although it is unclear which beta-blockers are most appropriate for PAD or CLI patients. Carvedilol and bisoprolol were generally used in this study, as high protective effects on the heart have been reported for drugs with b1 selectivity or a-blocking activity 5, 7, 19), lipid-soluble agents 20) and medications with no intrinsic sympathomimetic activity 21) in large-scale clinical studies. In addition, the use of long-acting drugs is desirable from the standpoint of internal medicine compliance, and this is one reason for the common daily clinical use of carvedilol and bisoprolol. Further examinations of the appropriate type and dose of beta-blockers are required, with monitoring of the heart rate and blood pressure as markers of treatment outcomes. Limitations There are several limitations associated with this study. First, the study design was retrospective, despite
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the use of a large-scale prospective database and propensity-matched scores, and there was considerable bias in many of the data assignments. Therefore, a prospective randomized investigation is needed to verify our findings. Second, the current results showed that treatment with beta-blockers did not affect the clinical outcomes of the patients. However, it is unclear if each specific beta-blocker had no effect compared to that observed in the patients treated without beta-blocker therapy, as the number of patients who received each drug was too small to conduct an analysis. Finally, the dose-dependent effects of beta-blockers were not investigated. Hence, further research of the dose is needed to clarify our findings. Although the preventive effects of beta-blockers on cardiac disease are clear based on widespread evidence of cardioprotection, the efficacy of beta-blockers in cases of CLI is uncertain, despite the fact that CLI causes life-threatening cardiac diseases and infections. Within the above limitations, the results of the current study indicate that beta-blockers have beneficial clinical effects in cases of CLI and are suitable for daily treatment in these patients. Conclusion The present findings suggest that the use of betablockers does not adversely affect the rates of AFS, limb salvage, all-cause mortality or MALE after EVT in patients with CLI. Taking into account contraindications, beta-blockers may be administered in patients judged to require this treatment, without worsening the clinical outcomes. Financial Support None. Conflicts of Interest None declared. References 1) Paravastu SC, Mendonca DA, da Silva A: Beta blockers for peripheral arterial disease. Eur J Vasc Endovasc Surg, 2009; 38: 66-70 2) Radack K, Deck C: Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med, 1991; 151: 1769-1776 3) Steg PG, Bhatt DL, Wilson PW, D’Agostino R Sr, Ohman EM, Röther J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto S; REACH Registry Investiga-
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