Large-vessel peripheral atherosclerosis is a frequent condition in the domain of cardiovascular disease. Prevalence of peripheral arterial disease (PAD) varies considerably among studies, ranging from 0.5% to about 10%, with age being a major determinant [1,2]. The relationship between prevalence of PAD and age has been well illustrated in an analysis of 2174 participants of at least 40 years of age in the National Health and Nutrition Examination Survey (NHANES) . The prevalence of PAD, defined as an ankle–brachial index (ABI) of less than 0.90 in either leg, was 0.9% between the ages of 40 and 49 years, 2.5% between the ages of 50 and 59 years, 4.7% between the ages of 60 and 69 years and 14.5% for age 70 and older .
The risk factors that may favour the development of PAD are similar to those that promote the development of coronary atherosclerosis and cerebral artery disease and, thus, it is not surprising that these conditions frequently occur together . As an example, in the Reduction of Atherothrombosis for Continued Health (REACH) registry, the 15.9% of patients with symptomatic atherothrombosis had polyvascular disease . In this subgroup, a significant proportion of patients showed the coexistence of PAD with coronary artery disease (CAD) or cerebrovascular disease  (Fig. 1).
In addition, PAD is an independent predictor of increased risk of cardiovascular and cerebrovascular death, with high blood pressure (BP) being a major modifiable risk factor [5,6]. This observation has been confirmed in the Systolic Hypertension in the Elderly Programme (SHEP) study  in which a low ABI (<0.9) in an older population as well as hypertension predicted a two-fold to three-fold increased risk of cardiovascular mortality.
Hypertension is present in up to 55% patients with PAD . It has been reported to increase the risk of intermittent claudication in men and women by 2.4-fold to 3.9-fold . After correction for potential confounders, SBP was associated with an odds ratio for PAD of 1.3 (95% confidence interval 1.2–1.5) for each 10 mmHg increase . Moreover, hypertension also increases the risk of cardiovascular disease complications and mortality in patients with established PAD .
Unfortunately, BP management in PAD tends to be poor . The PAD Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) programme , a multicentre, cross-sectional study conducted at 27 sites in 25 cities and 350 primary care practices throughout the United States, showed that hypertension is less often treated in new PAD (84%) compared with treatment of hypertension in individuals with cardiovascular disease (P < 0.001). Treatment of hypertension in patients with symptomatic PAD needs careful consideration because antihypertensive medication may cause unwanted effects potentially altering the clinical picture of PAD.
Among antihypertensive agents, β-blockers have been considered contraindicated in patients with concomitant intermittent claudication. Potential mechanisms explaining the adverse profile of β-blockers in PAD included blockade of β2-receptor-mediated skeletal muscle vasodilatation, leaving the α-tone unopposed, and reduced cardiac output .
However, recent experimental studies suggested that β-blockers may positively interfere with basic mechanisms involved in the development of atherosclerotic vascular disease during different phases of the disease process [11,12].
The inhibition by β1-selective β-blockade reduces adrenergic activity which is typically associated with an increased endothelial injury .
In addition, β-blockers may favourably influence the metabolism of arterial tissue [14,15]. Atherosclerotic tissue exhibits increased oxygen consumption as a consequence of which vasa vasorum develops within atherosclerotic lesions, leading to a deterioration of the mechanical stability of the atherosclerotic plaque. Lipid-containing foam cells in the atherosclerotic lesion have high oxygen consumption. Interestingly, the high oxygen consumption of these cells may be related to energy-dependent intracellular cholesterol cycle which is regulated and controlled by adrenergic receptors. β-Blockade might inhibit this cycle and reduces energy consumption in atherosclerotic tissue [14,15]. This speculative scenario may be particularly beneficial in later phases of the atherosclerotic process.
Recently, there was renewed interest in potential advantages of third-generation β-adrenergic receptor blockers such as carvedilol and nebivolol [12,16].
Nebivolol has the highest specificity for β1-receptors and vasodilator properties mediated by nitric oxide (NO) release . This is due to a direct stimulatory effect on the endothelial NO synthase. In addition, it shows antioxidant properties which may further impact on the pathophysiology and progression of cardiovascular disease [12,16]. In experimental models, it has been shown to have protective effects on ischaemia and reperfusion injury . It also increases, more than other β-blockers, coronary flow reserve in patients with ischaemic heart disease and nonischaemic dilated cardiomyopathy .
A meta-analysis of randomized controlled trials (RCTs) of β-blocker therapy in individuals with PAD showed that these agents did not adversely affect walking distance or intermittent claudication . Notably, in two studies metoprolol slightly increased walking distance in comparison with placebo [20,21]. Use of pindolol and labetalol, but not atenolol, was associated with a significant reduction in pain-free walking distance .
Recently, the Cochrane Peripheral Vascular Disease Group systematically reviewed the potential harms of β-blockers on claudication distance in patients with PAD and intermittent claudication . Six randomized, double-blind, placebo-controlled, cross-over trials were included in the analysis, with a total of 119 patients. β-Blockers studied were atenolol, propranolol, pindolol and metoprolol. None of the trials included in the analysis showed a statistically significant worsening effect of β-blockers on walking distance .
However, the trials included in the analysis were of poor quality, with the drugs being administered for short periods (10 days to 2 months). In addition, most were small trials recruiting between 10 and 20 participants, with the largest study enrolling 49 participants .
The controlled trial on the effect of nebivolol in PAD patients published in the current issue of the Journal of Hypertension  sheds new light in the grey areas left by previous RCTs in terms of methodological quality, number of participants, time of observation and type of comparator.
Briefly, this multicentre, prospective, randomized, double-blind, noninferiority trial examined the influence of nebivolol on the walking distance in patients with PAD (Fontaine stage II) and hypertension compared with an active treatment with hydrochlorothiazide (HCTZ) during a 24-week double-blind treatment period. It was also followed by a 4-week period without study medication in order to assess a possible rebound phenomenon on walking distance . Overall, 177 patients were randomized to study treatments. The intent-to-treat analysis was performed on 163 patients (nebivolol group = 84, HCTZ group = 79). The primary efficacy criterion was the percentage change in the initial claudication distance (ICD) between baseline and week 28 and the secondary efficacy criteria included absolute claudication distance (ACD).
Both nebivolol and HCTZ significantly reduced SBP. Nebivolol decreased SBP from 147.7 ± 10.6 to 140.0 ± 14.3 mmHg after 24-week treatment. HCTZ reduced SBP from 149.9 ± 10.4 to 140.5 ± 15.1 mmHg. ICD significantly increased by 28.3% from baseline to the end of the treatment in the nebivolol group and HCTZ exerted a comparable effect (26.5%, P = 0.83 vs. nebivolol). Similar results were obtained considering the ACD (15.8 vs. 20.2%, P = 0.51).
Notably, both treatments were well tolerated and there were no significant differences between groups with regard to the overall adverse events experienced and laboratory parameters .
Antihypertensive therapy should be administered to hypertensive patients with lower extremity PAD to reduce the risk of myocardial infarction (MI), stroke, congestive heart failure and cardiovascular death [1,2]. However, antihypertensive therapy may decrease limb perfusion pressure and potentially exacerbate symptoms of claudication. These possibilities should be taken into account when administering antihypertensive drugs to patients with PAD. However, most patients with intermittent claudication can tolerate therapy without symptoms worsening and should, therefore, be treated appropriately to reduce the risk of adverse cardiovascular events [1,2].
The major limitation to the use of β-blockers to treat hypertension in PAD is the lack of sound and conclusive evidence. On the contrary, there is no evidence of harm associated with β-blocker treatment in mild-to-moderate PAD and there is some evidence that β-blockers treatment in patients with concomitant CAD may improve cardiovascular outcomes [1,2]. Accordingly, the current guidelines of American College of Cardiology (ACC) and American Heart Association (AHA) for the management of patients with PAD  reinforce the notion that β-adrenergic blocking drugs are effective antihypertensive agents and are not contraindicated in patients with mild-to-moderate PAD (class I, level of evidence: A). A similar position is also endorsed by the Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease (TASC II) .
Although a patient-tailored approach toward using antihypertensive agents may be wise, the impact of comorbidity on treatment choices should be carefully considered by practising physicians. It is well known that patients with PAD may have concomitant CAD or other clinical conditions  which might have specific additional and compelling indications for the treatment with β-blockers. In plain words, β-blockers should be administered in patients with PAD who also have concomitant heart failure, previous MI, angina pectoris and atrial fibrillation or flutter to provide additional cardioprotection. In the absence of such concomitant conditions, β-blockers may be considered as add-on drugs to reach BP target (Fig. 2).
There is, to date, uncertainty about the choice of BP-lowering agents in PAD patients with hypertension. The impact of comorbidity should be considered to provide a specific additional indication for treatment, for example cardioprotection from β-blockade following acute MI or congestive heart failure. However, it is still unclear whether cardioprotection applies to β-blockade targeted at hypertension in PAD, beyond that conferred by other BP-lowering treatments.
In addition, β-blockers may have adverse metabolic effects (moderate elevation in plasma glucose concentration, increased insulin resistance and increased risk of new onset diabetes, reduced high-density lipoprotein–cholesterol and elevated triglycerides), with the exception of vasodilating β-blockers such as carvedilol and nebivolol [26,27].
For nebivolol, a decade of clinical experience in Europe provides support to its neutral effect on lipid and glucose metabolism and to its BP-lowering efficacy [26,27].
In terms of efficacy on BP, some studies suggested that nebivolol compares at the same level with other β-blockers, calcium channel antagonists and angiotensin-converting enzyme inhibitors [28–30]. Although these observations appear promising, outcome data from large studies in hypertension are currently not available. Nebivolol in patients with congestive heart failure is as well awaiting definitive answers. The results of the Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with heart failure (SENIORS) showed a 14% proportional reduction in all-cause mortality, but not in hospitalization after nebivolol therapy compared with placebo in patients with congestive heart failure . However, these data appear somewhat less favourable than those observed in other β-blocker trials .
Although data on a possible favourable effect of nebivolol on the development of atherosclerosis exist, further randomized controlled studies are needed to ultimately establish whether the potential additional antiatherosclerotic mechanisms of this third-generation β-blocker confer end-point benefits over other types of β-blocker in patients with PAD.
This study was funded in part by the Fondazione Umbra Cuore e Ipertensione - ONLUS, Perugia, Italy.
None of the authors of this study has financial or other reasons that could lead to a conflict of interest.
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