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Impact of betablockers on general and local outcome in patients hospitalized for lower extremity peripheral artery disease

The COPART Registry

Mirault, Tristan MD, PhDa,*; Galloula, Alexandre MDa; Cambou, Jean-Pierre MDb,c; Lacroix, Philippe MD, PhDd; Aboyans, Victor MD, PhD, FAHA, FESCe; Boulon, Carine MDb; Constans, Joel MD, PhDf; Bura-Riviere, Alessandra MD, PhDb; Messas, Emmanuel MD, PhD, FACC, FESCa

Section Editor(s): Calderon., Lindsay

doi: 10.1097/MD.0000000000005916
Research Article: Observational Study

Lower extremity peripheral artery disease (PAD) is one manifestation of atherosclerosis. Patients with PAD have an increased rate of mortality due to concurrent coronary artery disease and hypertension. Betablockers (BB) may, therefore, be prescribed, especially in case of heart failure. However, BB safety in PAD is controversial, because of presumed peripheral hemodynamic consequences of BB that could lead to worsening of symptoms in patients with PAD. In this context, we aimed to determine the impact of BB on all-cause and cardiovascular mortality and amputation rate at 1 year after hospitalization for PAD from the COPART Registry population. This is a prospective multicenter observational study collecting data from consecutive patients hospitalized for PAD in vascular medicine departments of 4 academic hospitals in France. Patients with, either claudication, critical limb ischemia or acute lower limb ischemia related to a documented PAD were included. We compared the outcomes of patients with BB versus those without BB in their prescription list at hospital discharge. The mean age of the study population was 70.9 years, predominantly composed of males (71%). Among the 1267 patients at admission, 28% were treated by BB for hypertension, prior myocardial infarction or heart failure. During their hospital stay, 40% underwent revascularization (including bypass surgery 29% and angioplasty 74%), 17% required an amputation, and 5% died. In a multivariate analysis, only prior myocardial infarction was found associated with BB prescription with an odds ratio (OR) of 3.11, P < 0.001. Conversely, chronic obstructive pulmonary disease or PAD with ulcer impeded BB prescription (OR: 0.57 and 0.64, P = 0.007; P = 0.001, respectively). One-year overall mortality of patients with BB did not differ from those without (23% vs. 23%, P = 0.95). The 1-year amputation rate did not differ either (4% vs. 6%, P = 0.14). Patients hospitalized for PAD with a BB in their prescription did not worsen their outcome at 1 year compared to patients without BB. Based on these safety data, prospective study could be conducted to assess the effect of BB on long-term mortality and amputation rate in patients with mild, moderate, and severe PAD.

aDepartment of Vascular Medicine, Hôpital européen Georges-Pompidou, assistance publique hôpitaux de Paris, APHP, Paris Descartes University, Sorbonne Paris Cite, PARCC, INSERM U970, Paris

bDepartment of Vascular Medicine, Rangueil Hospital, Institute of Molecular Medicine of Rangueil, INSERM U858

cDepartment of Biostatistics, Rangueil Hospital, Toulouse

dDepartment of Thoracic and Cardiovascular Surgery and Angiology, Dupuytren University Hospital, Limoges

eDepartment of Cardiology, Dupuytren University Hospital, INSERM U1094, Limoges

fDepartment of Vascular Medicine, Saint-André Hospital, Bordeaux, France.

Correspondence: Tristan Mirault, Department of Vascular Medicine, Hôpital européen Georges-Pompidou, assistance publique hôpitaux de Paris, 20 rue Leblanc, 75015 Paris, France (e-mail:

Abbreviations: 95% CI = 95% confidence interval, ABI = ankle brachial index, ACE = angiotensin converting enzyme, ARB = angiotensin receptor blocker, BB = betablockers, CLI = critical limb ischemia, COPD = chronic obstructive pulmonary disease, LVEF = left ventricular ejection function, OR = odds ratio, PAD = peripheral artery disease.

TM and AG contributed equally as co–first authors.

Funding/support: This study has been supported by the national program PHRC 2007 DIRC SOOM. The COPART Registry is supported by the French Vascular Medicine Society.

The authors have no funding and conflicts of interest to disclose.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Received August 3, 2016

Received in revised form November 22, 2016

Accepted December 28, 2016

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1 Introduction

Lower extremity peripheral artery disease (PAD) is a common manifestation of atherosclerosis and is associated with an increased risk of coronary artery disease and cardiovascular death.[1–3] A substantial proportion of patients aged over 65 years develop PAD, around 2% if we consider intermittent claudication symptoms, and over 10%, when measuring a low ankle brachial index (ABI) (≤0.90). [4–6] More broadly, prevalence for PAD was 10.69% in a large sample of almost 12 million United States of America insured citizens, and its annual incidence was 2.35%.[7] PAD has a poor prognosis and represents a heavy burden in cardiovascular morbidity and mortality. A 5-year follow-up study found a 33.2% mortality rate in PAD patients and an even more higher rate within 10 years, with 62% of death in men and 33% in women.[8,9] The majority of patients with PAD not only combine multiple cardiovascular risk factors at the time of diagnosis but also present a polyvascular disease, which contribute to such a high risk of death. However, major cardiovascular events remain substantial among patients with isolated PAD. According to a large meta-analysis, the 10-year mortality rate in men with isolated low ABI was 18.7%, and 12.6% in women.[1] Globally, PAD is associated with virtually twice the 10-year total mortality, cardiovascular mortality, and major coronary event rates compared with those without PAD in each Framingham risk score category.[1]

While PAD patients often have concomitant diseases requiring betablockers (BB) (e.g., coronary artery disease, heart failure, or hypertension), their use is still controversial in this population, especially in case of critical limb ischemia (CLI), a more severe condition with a 1-year mortality rate over 20%.[10–12] In real life, Narins et al[13] noticed in a prospective cohort that following myocardial infarction, the added presence of intermittent claudication was associated with an underuse of BB therapy and was a strong independent predictor of recurrent cardiovascular events. The concept that beta-receptor antagonism may worsen limb symptoms in patients with PAD is based on several potential mechanisms, including reduction of cardiac output, induction of reflex sympathetic activity, and an imbalance of alpha and beta agonism in the peripheral vasculature, resulting in vasoconstriction and impaired peripheral perfusion. Concerns have therefore emerged regarding the potential for BB to worsen limb or general prognostic in PAD.[14] Moreover, evidence supporting or refuting the use of BB in PAD from meta-analyses remains elusive.[15–17] Radack et al concluded that BB could probably be used safely in PAD patients,[15] whereas meta-analysis from Miyajima et al showed that there was a significant worsening in maximal walking distance and initial claudication distance in patients receiving BB.[16] The latest Cochrane systematic review on this subject concludes with the absence of evidence supporting that BB adversely affect walking distance in people with intermittent claudication. However, the authors recommend that BB should be used with caution, in the case of CLI for which acute lowering of blood pressure is contraindicated. They underline that no large published trials are available and recommend high-quality, randomized trials to be conducted to evaluate the role of BB in patients with mild, moderate, and severe PAD.[17] In this context, we carried out a study, aimed at assessing BB prescription in patients hospitalized for PAD from the COPART Registry and analyzing their impact on 1-year morbidity and mortality.

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2 Methods

The COPART Registry is a multicenter registry, collecting exhaustive data prospectively on consecutive patients hospitalized for PAD in 4 academic centers in France since May 17, 2004 to July 15, 2010 (Bordeaux, Limoges, Paris, and Toulouse). Details regarding the COPART Registry have already been published.[18] In each vascular center, care to patients was provided according to the usual practice without any change in the management strategy. Initial clinical history, disease characteristics, and therapeutic data were collected. The enrolled patients gave their informed consent to participate. This study was approved by the institutional review board of the Toulouse University Hospital.

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2.1 Inclusion criteria

Each patient required the following criteria to be included: age ≥18 years; consent to participate to the registry and a first hospitalization specifically for clinical PAD of atherosclerotic origin. Clinical presentations could be severe claudication—associated with an ABI <0.90 or >1.30 or, a lower limb arterial stenosis >50% on duplex ultrasound, angiography or angiography computerized tomography in the case of normal ABI at rest—CLI with or without ulceration or gangrene and acute lower limb ischemia related to a documented PAD with significant arterial stenosis. Staging of patients’ PAD was established according to The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines.[10]

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2.2 Exclusion criteria

Patients with arterial occlusive disease not related to atherosclerosis, acute lower limb ischemia of embolic origin and patients refusing to participate were excluded from the registry.

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2.3 Follow-up

After the initial hospitalization, all patients were followed up for at least 12 months. For this purpose, mortality data at registrar's offices have been consulted, and nonfatal events were retrieved through the hospitals’ files, mailing, or phone contacts to the physicians or the patients if necessary. The primary outcome for this study was the overall mortality during the 1-year follow-up. Secondary outcomes were cardiovascular mortality and occurrence of amputation.

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2.4 Statistical analysis

Discrete variables are presented as number and percentage, and continuous variables as mean and standard deviation. Comparisons were made using chi-square test (or Fisher exact tests, when appropriate) for discrete variables, and Student t test for continuous variables. Multivariate analysis was performed using linear logistic regression to calculate odds ratio (OR) and 95% confidence interval (95% CI) for outcome events: overall mortality, cardiovascular mortality, and amputation. All subsequent P values are reported for 2-tailed tests with a 5% threshold. All analyses were performed with SAS statistical software version 9.2 (SAS Inc., Cary, NC).

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3 Results

Over a 6-year-period, 1267 patients were included in this study. Table 1 shows the study population characteristics.

Table 1

Table 1

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3.1 At admission

At entry, 339 (27%) patients were newly diagnosed with PAD. One quarter of the patients presented with claudication (PAD grade 0–I) and 2/3 with CLI (PAD grades II–III). BB were present for 1/4 of the patients at admittance (28%). History of hypertension, prior myocardial infarction or heart failure were associated with BB prescription: 85% versus 69%, 38% versus 17%, 17% versus 10%, as compared to those without this condition, P < 0.001, P < 0.001, P = 0.004, respectively. Proportion of patients with BB and PAD grade III was significantly lower than patients with any other PAD grade (P = 0.02).

In multivariate analysis, history of hypertension or prior myocardial infarction were independent factors for BB prescription with OR (95% CI) of 2.60 (1.75–3.86), P < 0.001 and 3.02 (2.15–4.25), P < 0.001, respectively. History of asthma or chronic obstructive pulmonary disease (COPD) and PAD grade III were associated with lower rates of BB prescription at admittance with OR (95% CI) of 0.57 (0.37–0.90), P = 0.02 and 0.55 (0.40–0.75), P < 0.001, respectively.

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3.2 At discharge

A revascularization (including bypass surgery 29% and angioplasty 74%) has been performed in 40% of the cases before discharge. Nonetheless, the proportion of patients who required amputation was 17%. During hospitalization, 66 (5%) subjects died. At discharge patients received a prescription with antiplatelet therapy in 81%, vitamin K antagonists in 14%, statins in 71%, angiotensin converting enzyme (ACE) inhibitors in 42%, angiotensin receptor blocker (ARB) in 18%, and BB in 27%. For consistent comparisons, we restrained the analysis of cardiovascular treatment changes during hospitalization to the 928 patients with already known PAD at entry and still alive at hospital discharge (Table 2). Antiplatelet therapy, statin, and ACE inhibitor prescriptions significantly increased from admittance to discharge (P < 0.001) but not the BB prescription.

Table 2

Table 2

History of hypertension, prior myocardial infarction or coronary artery disease, were associated with BB prescription (81% vs 67%, 35% vs 15%, and 65% vs 28%, P < 0.001 respectively) (Table 3). Conversely, BB were less prescribed in the case of asthma or COPD (11% vs 16%, P = 0.03), PAD grade III (45% vs 57%, P = 0.003), or in elderly. There was no significant difference between patients with and those without BB for sex, ABI, renal failure, or diabetes. Neither other drugs prescription nor the revascularization procedure were influenced by the presence of BB, except for ARB (22% vs 17%, P = 0.04). Patients who underwent amputation during their hospitalization were less treated by BB (13% vs 19%, P = 0.02). In multivariate analysis (Fig. 1), prior myocardial infarction favored BB prescription with an OR (95% CI) of 3.11 (2.29–4.21), P < 0.001. History of asthma or COPD and PAD grade III had a negative relationship with OR (95% CI) of 0.57 (0.37–0.85), P = 0.007 and 0.64 (0.49–0.84), P = 0.01, respectively.

Table 3

Table 3

Figure 1

Figure 1

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3.3 Follow-up at 1 year

At 1 year, 271 patients (23%) died, including 160 (13%) from cardiovascular origin (Table 4). Advanced age and prior myocardial infarction were independent factors of overall mortality (Fig. 2). Overall and cardiovascular mortalities did not differ according to BB status: OR (95% CI) 1.34 (0.92–1.97), P = 0.13 and 1.08 (0.77–1.50), P = 0.65, respectively.

Table 4

Table 4

Figure 2

Figure 2

At 1 year, 67 patients (6%) underwent amputation, with no difference between BB users and nonusers, respectively, 4% versus 6% (P = 0.14), OR (95% CI) 0.63 (0.33–1.19), P = 0.16.

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4 Discussion

In this study, we found that patients hospitalized for PAD and treated by BB at hospital discharge did not worsen their outcome at 1 year compared to patients not treated by BB. Indeed, neither overall mortality, nor cardiovascular mortality, or amputation rates were impacted by the presence of BB in the prescription list. Different meta-analyses concluded with the absence of evidence supporting that BB adversely affect PAD patients with intermittent claudication.[15–17] But the selected studies only addressed the effect of BB on limb impairment and were restrained to patients with intermittent claudication.[19–28] Deleterious effects of BB are specifically suspected in CLI, which may explain the lower rate of BB prescription in PAD grade III patients in our study. Predictors of BB prescription were indeed essentially prior myocardial infarction, and in a lesser extent the history of hypertension or coronary artery disease. On the contrary, severe PAD (PAD grade III) and asthma/COPD impeded BB prescription.

However, restraints on BB prescription were not merely related to the fear of PAD worsening in the most compromised cases. Only 33% of the patients with heart failure history had BB in their prescription list. Similarly, only 47% of the patients with myocardial infarction in their medical history were treated by BB. Overall, BB were underused in this study population, according to the European guidelines.[29–31] As a reminder, without contraindication, BB are recommended for patients with a chronic heart failure and left ventricular ejection function (LVEF) <40%,[29] or a history of acute coronary syndrome without persistent ST-segment elevation and LVEF < 40%.[31] BB may also be the first line antiangina therapy in stable coronary artery disease.[30] This underuse may represent a bias on the outcome at 1 year in our study, but the phenomenon is commonly and broadly noticed in the literature.[32–34]

We noticed a trend for a lower amputation rate in patients treated by BB at 1 year, but the difference was not statistically significant. This is consistent with the results reported in a recent Danish study, where 16945 symptomatic PAD patients were included and treated either by primary vascular surgery or by endovascular reconstruction. Among them, the 7828 BB users presented a reduced risk of major amputation: hazard ratio (95% IC) 0.80 (0.70–0.93).[35]

In our multicenter cohort of hospitalized patients for PAD, demographic characteristics, cardiovascular risk factors, and medical history were comparable to others PAD cohort studies.[2,36–39] These cohorts reported between 286 and 8273 PAD patients based on ABI < 0.9 or history of amputation or peripheral revascularization. The mean age ranged from 69.2 to 73.9 years, men represented 46.0% to 81.2%, current smokers 15.9% to 39.3%, diabetes 25.9% to 44.2%, hypertension 63.4% to 81.0%, and hyperlipidemia 57.2% to 66.7%. Other vascular beds were affected in these PAD patients with cerebrovascular disease in 12.6% to 23.0% and coronary artery disease in 24.1% to 51.7%.[2,36–39] However, clinical presentation of our patients was more severe: only 1/4 presented with intermittent claudication, whereas the 2/3 had CLI and 10% an acute limb ischemia. This may explain that the 22% 1-year mortality rate in our study was higher than in other similar studies (4%–8%).[8,40,41] We found that presence of BB was not associated with an increased risk of mortality. In other words, it also means that BB did not decrease the mortality rate, whereas 2/3 of the deaths were of cardiovascular origin. In previous studies, including symptomatic PAD patients with prior myocardial infarction, BB were associated with a lower risk of recurrence of acute myocardial infarction.[13,42] In the Danish study, BB were not associated with a higher mortality rate, but were associated with an increased risk of acute myocardial infarction and/or stroke during the follow-up period.[35] In our study, we did not find any increase of cardiovascular fatal events associated with BB.

Our study has some limitations. This is an observational study, not a randomized trial. Findings should, therefore, be addressed with usual caution, although we made multivariate analysis to take into account factors affecting BB prescription. Details on what BB and what dosage are not provided in our study. We are aware that BB have different pharmacokinetic and pharmacodynamic properties, which introduce heterogeneity in the analysis. However, the data collection was not designed to collect prospectively these details. Moreover, we used patient's prescription list as a proxy for actual drug use, but we had no information regarding patient's compliance to treatment. While our registry is one of the largest ones for patients hospitalized for PAD, we were unable to perform subgroup analyses because of statistical power weakening in smaller groups. However, we are confident regarding exhaustiveness in the follow-up of death and amputation. Not only because the death criteria were easily retrieved, and the amputations were done in the participating hospitals, but also because the accuracy of the data sources in the COPART Registry was previously described as good.[18,43,44]

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5 Conclusion

Patients hospitalized for PAD could safely carry on with their BB treatment with no increase in the 1-year overall mortality or the amputation rate. Based on these safety data, and aware of the high cardiac mortality rate in PAD, a high-quality, prospective randomized trial would be of interest to evaluate the role of BB in patients with mild, moderate, and severe PAD on mortality, regardless the coronary artery disease history. As witnessed in this study, where PAD grade III was an impediment to BB prescription, attention should be paid to CLI in further studies, in order to establish the safety of BB in this severe condition.

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adult; amputation; betablockers; mortality; peripheral artery disease

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