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-Blockers in Patients With Intermittent Claudication and Arterial Hypertension: Results From the Nebivolol or Metoprolol in Arterial Occlusive Disease Trial
Abstract
The use of β-receptor blockers in peripheral arterial disease is controversial for their impact on vasomotor tone. The β-blocker nebivolol possesses vasodilating, endothelium-dependent, NO-releasing properties that might be beneficial in peripheral arterial disease. The aim of the study was to evaluate the effects and tolerability of nebivolol in comparison with metoprolol in these patients. A total of 128 patients with intermittent claudication and essential hypertension were included and double-blind randomized to receive 5 mg of nebivolol (N=65) or 95 mg of metoprolol (N=63) once daily. End points were changes in ankle-brachial index, initial and absolute claudication distance, endothelial function assessed by flow-mediated dilatation of the brachial artery, blood pressure, and quality of life using the claudication scale questionnaire. End point analysis was possible in 109 patients (85.2%). After the 48-week treatment period, ankle-brachial index and absolute claudication distance improved significantly in both patient groups (P<0.05 for both), with no difference across treatments. A significant increase of initial claudication distance was found in the nebivolol group. Adjusted mean change of initial claudication distance was 33.9% after nebivolol (P=0.003) and 16.6% after metoprolol (P=0.12) treatment. Quality of life was not influenced by either treatment, and there was no relevant change in flow-mediated dilatation in patients treated with nebivolol or metoprolol (P=0.16). Both drugs were equally effective in lowering blood pressure. In conclusion, β-blocker therapy was well tolerated in patients with intermittent claudication and arterial hypertension during a treatment period of ≈1 year. In the direct comparison, there was no significant difference between nebivolol and metoprolol.
... [40] compared nebivolol 5 mg daily versus atenolol 100 mg daily (if blood pressure was outside the therapeutic target, hydrochlorothiazide 12.5 mg daily was added) for 12 weeks and included individuals between 19 and 75 years of age; Kamp et al. [41] compared nebivolol 5 mg daily versus atenolol 100 mg daily (without an association with other antihypertensive drugs) for 2 weeks and included individuals between 29 and 60 years of age; Pasini et al. [42] compared nebivolol 5 mg daily versus atenolol 100 mg daily (without an association with other antihypertensive drugs) for 4 weeks and included individuals aged 56.0 ± 8.6 years; Pasini et al. [43] compared nebivolol 5 mg daily versus atenolol 100 mg daily (without an association with other antihypertensive drugs) for 4 weeks and included individuals aged 55.9 ± 10 years; Susmitha and Naganjani [44] compared nebivolol 5 mg daily versus atenolol 50 mg daily (without an association with other antihypertensive drugs) for 12 weeks and included individuals between 18 and 60 years of age (75% of patients were aged between 31 and 50 years). (5) Metoprolol: Espinola-Klein et al. [45] compared nebivolol 5 mg daily versus metoprolol 95 mg daily (without an association with other antihypertensive drugs) for 48 weeks and included individuals aged 66.7 ± 8.3 years (nebivolol group) and 65.9 ± 7.9 years (metoprolol group); Fici et al. [46] compared nebivolol 5 mg daily versus metoprolol 100 mg daily (without an association with other antihypertensive drugs) for 6 months and included individuals aged 50.24 ± 6.1 years (nebivolol group) and 52.48 ± 5.59 years (metoprolol group); Hayek et al. [47] compared nebivolol (medium dose) 11.7 mg daily versus metoprolol (medium dose) 123 mg daily [only two patients (in a total of 38 individuals of this arm) had an association of amlodipine and hydrochlorothiazide in the therapeutic regimen due to blood pressure outside the therapeutic target] for 24 weeks and included individuals aged 55 ± 10 years. Kampus et al. [48] compared nebivolol 5 mg daily (12 of 30 patients also used hydrochlorothiazide 12.5-25 mg daily in combination) versus metoprolol 70 mg (medium dose) daily (9 of 33 patients used hydrochlorothiazide 12.5-25 mg daily in combination) for 1 year and included individuals between 30 and 65 years of age; Serg et al. [50] compared nebivolol 5 mg daily (12 of 30 patients used hydrochlorothiazide 12.5-25 mg daily in combination) versus metoprolol 50 mg daily (9 of 33 patients used hydrochlorothiazide 12.5-25 mg daily in combination) for 54 weeks and included individuals between 30 and 65 years of age. ...
... In this case, the numbers shown to the left of the studies represent: (4) Atenolol: Bhosale et al. [39] compared nebivolol 5 mg daily versus atenolol 50 mg daily (without an association with other antihypertensive drugs) for 12 weeks and included individuals between 18 and 65 years of age; Grassi et al. [40] compared nebivolol 5 mg daily versus atenolol 100 mg daily (if blood pressure was outside the therapeutic target, hydrochlorothiazide 12.5 mg daily was added) for 12 weeks and included individuals between 19 and 75 years of age. (5) Metoprolol: Espinola-Klein et al. [45] compared nebivolol 5 mg daily versus metoprolol 95 mg daily (without an association with other antihypertensive drugs) for 48 weeks and included individuals aged 66.7 ± 8.3 years (nebivolol group) and 65.9 ± 7.9 years (metoprolol group); Uhlir et al. [65] compared nebivolol 5 mg daily versus metoprolol 200 mg daily (without using association with other antihypertensive drugs) for 12 weeks and included individual adults over 18 years of age. No other β-blockers were added because no clinical trials that met the inclusion criteria for this work (and that compared the use with nebivolol) were identified results, nebivolol was even more effective in controlling DBP. ...
Introduction:
Cardiovascular diseases are the main cause of mortality worldwide, and systemic arterial hypertension is associated with a large number of these cases. The objective of health professionals and health policies should be searching for the best therapeutics to control this disease. A recent consensus indicated that β-blockers have recently lost their place in initial indications for the treatment of systemic arterial hypertension and are now more indicated for the treatment of hypertension in association with other clinical situations such as angina, heart failure and arrhythmia; however, it is known that this approach was based on studies that evaluated older β-blockers such as atenolol.
Objective:
The main objective of this study was to perform a systematic review with subsequent meta-analysis on the use of nebivolol for hypertensive disease treatment, comparing it with drugs of the main antihypertensive classes.
Methods:
This systematic review was based on a search of the MEDLINE (via Pubmed), Scopus, Cochrane, International Pharmaceuticals Abstracts (IPA), and Lilacs databases for randomized and double-blind clinical trials. In addition, we also searched for gray literature studies, to 31 July 2015. Next, a cumulative meta-analysis was performed, with studies being added in a sequential manner, evaluating their impact on the combined effect. For this project, we only meta-analyzed direct comparisons of random effect.
Results:
Overall, 981 clinical trials were included in this systematic review. After careful analysis, 34 randomized and double-blind clinical trials were included to investigate the efficacy of nebivolol on systolic (SBP) and diastolic blood pressure (DBP) control and adverse effects. The study population comprised 12,465 patients with systemic arterial hypertension (SAH) aged between 18 and 85 years; 17% of subjects were of Black ethnicity, approximately 55% were men, and almost 10% had diabetes. In SBP management, nebivolol was superior to other β-blockers and diuretics and showed no difference in efficacy when compared with angiotensin receptor blockers or calcium channel blockers. There were insufficient studies on angiotensin-converting enzyme inhibitors for adequate comparison of both SBP and DBP control. For DBP control, nebivolol was more efficient than other β-blockers, angiotensin receptor blockers, diuretics, and calcium channel blockers.
Discussion:
Nebivolol is a third-generation β-blocker with additional capabilities to improve blood pressure levels in patients with arterial hypertension, because it acts by additional mechanisms such as endothelium-dependent vasodilation associated with L-arginine and oxide nitric acid, nitric oxide activity on smooth muscle cells, decreasing platelet aggregation, and leukocyte adhesion in the endothelium, decreasing oxidative stress. Although nebivolol has shown good results in controlling hypertension in this study (with few adverse events when compared with placebo treatment) and has an unquestionable benefit in individuals with heart failure (mainly with reduced ejection fraction), there is a lack of studies proving the benefit of this drug for controlling hypertension and reducing clinical outcomes such as cardiovascular (or general) mortality, acute myocardial infarction, or stroke.
Conclusions:
Nebivolol demonstrated at least similar control of blood pressure levels in hypertensive individuals when compared with drugs of the most used classes. In addition, in relation to the control of arterial hypertension, studies with clinical outcomes should be performed to ensure the use of this drug in detriment to others with these well-established results.
... Высказывались опасения по поводу того, что антигипертензивная терапия может снизить перфузию конечностей. Однако множество исследований показало, что снижение повышенного АД, в том числе использование высокоселективных бета-блокаторов, не усугубляет симптомы динамического нарушения кровообращения или нарушение функционального статуса у пациентов с ЗАНК [44][45][46]. ...
... В двойном слепом рандомизированном клиническом исследовании было проведено сравнение эффективности препаратов метопролол и небиволол у 128 пациентов с перемежающейся хромотой и артериальной гипертензией, ранее не получавших β-блокаторы [46]. ...
... A study carried out by Christine Espinola-Klein et al [25] to evaluate the effects and tolerability of Nebivolol in comparison with Metoprolol in these patients. In conclusion, β-blocker therapy was well-tolerated in patients with peripheral vascular disease and arterial hypertension during a treatment period of 1 year. ...
... In conclusion, β-blocker therapy was well-tolerated in patients with peripheral vascular disease and arterial hypertension during a treatment period of 1 year. In the direct comparison, there was no significant difference between Nebivolol and Metoprolol [25]. A meta-analysis carried out by Van Bortel LM et al. to evaluate the efficacy and tolerability of Nebivolol compared with other anti-hypertensive drugs. ...
Background: Cost of any drugs can not only judge by simple their price but at the same time efficacy, safety and quality of drug itself determined the actual cost of a drug. Aims and Objectives: Aim of the present study is to compare the cost-effectiveness and safety of Nebivolol and Metoprolol in order to reduce blood pressure. Materials and Methods: The present study includes a total of 90 randomly selected patients with the age ranges from 25 to >65 years (mean= ±12). The drug Metoprolol and Nebivolol is given to the 56 and 34 randomly selected patients respectively to observe the effect and tolerability of drug in respect to their costs. Cost effectiveness was calculated and compared by 1mm fall of Hg by both drugs. Safety and effectiveness was observed clinically. Results: In this present study we found that the Nebivolol is more cost effective, tolerable and safe, as compare to Metoprolol in reducing 1mmHg blood pressure. Conclusions: In the present study we concluded that Nebivolol is Pharmaco-economically better drug than Metoprolol. This may affect the patients economically in long term use.
... Postulowano również zalety nebiwololu jako b-adrenolityku wykazującego dodatkowe działanie naczyniorozszerzające [1], ale dowody dotyczące potencjalnej przewagi b-adrenolityków o działaniu naczyniorozszerzającym nad konwencjonalnymi b-adrenolitykami u pacjentów z LEAD są jednak bardzo ograniczone. Metoprolol i nebiwolol porównano w próbie klinicznej z randomizacją, przeprowadzonej metodą podwójnie ślepej próby, z udziałem 128 pacjentów z chromaniem przestankowym i nadciśnieniem tętniczym, którzy wcześniej nigdy nie byli leczeni b-adrenolitykiem [71]. Po 48 tygodniach leczenia stwierdzono dobrą tolerancję obu leków, taki sam efekt hipotensyjny oraz poprawę maksymalnego dystansu chodu i ABI w obu grupach, bez istotnych różnic między grupami. ...
... BBs can be safely used for HT coexisting with LEAD and specific indications. The guideline emphasises that especially those with vasodilatory effects may prolong the distance in the intermittent claudication and improve the clinical condition of the patient [228,229]. ...
... The 2023 ESH guidelines regard these effects as therapeutic disadvantages that may reduce or avoid the use of BBs in specific conditions or in some patients but do not consider them a reason to exclude BBs from the main antihypertensive treatment algorithm. In this context, relevant arguments are that, (1) some side effects of BBs have been overestimated 53,54 ; (2) it is now widely accepted that BBs can be used with no substantial safety problems for respiratory function or lower limb perfusion 55,56 in obstructive lung disease and peripheral artery disease, where they may provide a better protection against coronary disease, which is common in these patients; (3) drug-related and between-drug differences in side effects are likely to be minimized by the combination treatment recommended by the 2023 ESH guidelines for most patients with hypertension, because side effects are dose-dependent and, in drug combinations, drugs are usually used at lower doses; (4) use of BBs is well established in several cardiovascular conditions frequently associated with and favored by hypertension (MI, angina pectoris, HF, atrial fibrillation, subaortic stenosis, long-QT syndrome, coronary bypass surgery, aortic dissection, aneurysm of the ascending or abdominal aorta, heart rate >80 bpm, etc.), in which they relieve symptoms and play a life-saving role; (5) the number of patients with hypertension in need of BBs is even larger if one considers that these drugs can be important in women with a child-bearing potential age as well as in hypertension disorders of pregnancy, where blockers of the renin-angiotensin system are contra-indicated. Furthermore, in clinical practice prescription of BBs extends to diseases that do not primarily involve the cardiovascular system, but in which BBs exert a favorable effect on their symptoms and signs 57 ; (6) the worse tolerability and the other inconveniences of BBs can be minimized by the new β-blocker generation, that is, by BBs with higher β-1 selectivity and an additional vasodilator effect 58 ; and (7) although rarely considered by guidelines, it may not be of marginal interest that BBs are a pathophysiological appropriate treatment because hypertension is characterized by sympathetic activation from its early to its late and complicated stages, to which it contributes with both BPdependent and BP-independent detrimental influences. ...
We address the reasons why, unlike other guidelines, in the 2023 guidelines of the European Society of Hypertension β-blockers (BBs) have been regarded as major drugs for the treatment of hypertension, at the same level as diuretics, calcium channel blockers, and blockers of the renin-angiotensin system. We argue that BBs, (1) reduce blood pressure (the main factor responsible for treatment-related protection) not less than other drugs, (2) reduce pooled cardiovascular outcomes and mortality in placebo-controlled trials, in which there has also been a sizeable reduction of all major cause-specific cardiovascular outcomes, (3) have been associated with a lower global cardiovascular protection in 2 but not in several other comparison trials, in which the protective effect of BBs versus the other major drugs has been similar or even greater, with a slightly smaller or no difference of global benefit in large trial meta-analyses and a similar protective effect when comparisons extend to BBs in combination versus other drug combinations. We mention the large number of cardiac and other comorbidities for which BBs are elective drugs, and we express criticism against the exclusion of BBs because of their lower protective effect against stroke in comparison trials, because, for still uncertain reasons, differences in protection against cause-specific events (stroke, heart failure, and coronary disease) have been reported for other major drugs. These partial data cannot replace global benefits as the main deciding factor for drug choice, also because in the general hypertensive population whether and which type of event might occur is unknown.
... Tedaviye genel KY popülasyonunda olduğu gibi en düşük dozdan (1.25 mg) başlanır (Tablo 1). 17 Erektil disfonksiyon (ED) komorbiditesi olan KY hastalarında β-bloker kullanımı: β-bloker kullanan KY hastalarında bireysel β-bloker kullanımı dikkate alınarak yapılan ED prevalansı ve şiddetinin değerlendirilmesi, atenolol, bisoprolol veya nebivolol ile tedavi edilen ED hastalarının neredeyse %50'sinin hafif ED'ye sahip olduğunu, oysa karvedilol veya metoprolol ile tedavi edilenlerin yüksek oranda orta veya şiddetli ED göstermiştir. Buradan yola çıkarak ED komorbiditesi olan KY hastalarında en düşük dozdan, yani günde 1,25 mg'dan başlanarak bisoprolol ve nebivolol gibi ajanların tercih edilmesi önerilmektedir (Tablo 1). ...
ZET Genel olarak kardiyoprotektif olarak kabul edilen β-blokerler kalp yetersizliğinde (KY) hastalı-ğın ilerlemesini yavaşlatır, yaşam kalitesini iyileştirir, hastaneye yatışları ve mortaliteyi azaltır. Sistolik disfonksiyonu olan tüm hastalarda semptomların şiddetine bakılmaksızın beta-blokerler standart tedavi olarak önerilmektedir. Heterojen terapötik etkiye sahip β-blokerler, β1 veya β2 reseptörleri için farklı se-çiciliğe sahiptir, bazıları intrinsik sempatomimetik aktivite ve α adrenoseptörleri üzerinde bazı ek etki-ler gösterir veya nitrik oksit salınımını destekler. KY hastalarında β-blokerlerin yetersiz kullanımı başarısız tedavi sonucu ile ilişkilendirilir. β-blokerler ile tedaviye en düşük dozla başlanır ve hastanın du-rumuna göre artırılarak hedef doza veya maksimum tolere edilebilir doza ulaşılır. Tedavide başarı için hastaya uygun olan β-blokeri seçmek önemlidir. Hastaya uygun β-bloker seçiminde komorbiditelerin varlığının göz önünde bulundurulması ve tolere edilebilen maksimum doza ulaşılması β-blokerlerin olumlu prognostik rolünün artırılmasında önemli hedeflerdir. Ejeksiyon fraksiyonu azalmış kronik KY'de beta bloker olarak karvedilol, metoprolol veya bisoprolol önerilirken. komorbid astım veya kronik obs-trüktif akciğer hastalığı olan KY hastalarında sadece β1-selektif ajanlar tercih edilir. Anah tar Ke li me ler: Kalp yetersizliği; beta blokerler; beta-reseptörler ABS TRACT β-Blockers, generally considered cardioprotective, slow the progression of heart failure (HF), improve quality of life, reduce hospitalizations and mortality. Beta-blockers are recommended as standard therapy in all patients with systolic dysfunction, regardless of the severity of symptoms. β-blockers with heterogeneous therapeutic effect have different selectivity for β1 or β2 receptors, some show intrinsic sympathomimetic activity and some additive effects on α-adrenoceptors or promote nitric oxide release. Inadequate use of β-blockers in patients with HF is associated with unsuccessful treatment outcome. Treatment with β-blockers is started with the lowest dose and increased according to the patient's condition to reach the target dose or the maximum tolerable dose. It is important to choose β-blocker that are appropriate for the patient for success in treatment. Considering the presence of comor-bidities in the selection of the appropriate β-blocker for the patient, and reaching the maximum tolerated dose, are important targets to increase the favorable prognostic role of β-blockers. While carvedilol, metoprolol or bisoprolol are recommended as beta-blockers in chronic HF with reduced ejection fraction, only β1-selective agents are preferred in HF patients with comorbid asthma or chronic obstructive pulmonary disease.
... Dlatego można je stosować u pacjentów z nadciśnieniem tętniczym i LEAD przy współistnieniu specyficznych wskazań. Co ważne, obowiązujące wytyczne postępowania w CLTI jednoznacznie podkreślają, że beta-ad-renolityki, zwłaszcza te o działaniu wazodylatacyjnym (nebiwolol, karwedilol) [158], mogą wydłużać dystans chromania przestankowego i poprawiać stan kliniczny [159]. Zważywszy na zalecenie bezterminowego ich przyjmowania u chorych z przewlekłym zespołem wieńcowym czy HFrEF, modyfikacja wspomnianych wcześniej zaleceń stanowi bardzo korzystną zmianę podejścia do tej grupy leków [156], umożliwiając ich zastosowanie bez obaw i przeciwwskazań u osób z licznymi schorzeniami przewlekłymi powszechnie współwystępującymi szczególnie u osób starszych. ...
... A RCT including 128 patients with IC and hypertension studied metoprolol and nebivolol. Both drugs were well-tolerated and improved WD especially nebivolol (improvement in pain free WD +34% (p < 0.003) vs. +17% for metoprolol p < 0.12) [130]. ...
The thrombotic mechanism, being common to peripheral arterial disease (PAD), acute myocardial infarction (AMI), and stroke, is responsible for the highest number of deaths in the western world. However, while much has been done for the prevention, early diagnosis, therapy of AMI and stroke, the same cannot be said for PAD, which is a negative prognostic indicator for cardiovascular death. Acute limb ischemia (ALI) and chronic limb ischemia (CLI) are the most severe manifestations of PAD. They both are defined by the presence of PAD, rest pain, gangrene, or ulceration and we consider ALI if symptoms last less than 2 weeks and CLI if they last more than 2 weeks. The most frequent causes are certainly atherosclerotic and embolic mechanisms and, to a lesser extent, traumatic or surgical mechanisms. From a pathophysiological point of view, atherosclerotic, thromboembolic, inflammatory mechanisms are implicated. ALI is a medical emergency that puts both limb and the patient’s life at risk. In patients over age 80 undergoing surgery, mortality remains high reaching approximately 40% as well as amputation approximately 11%. The purpose of this paper is to summarize the scientific evidence on the possibilities of primary and secondary prevention of ALI and to raise awareness among doctors involved in the management of ALI, in particular by describing the central role of the general practitioner.
... iv. Some earlier specific concerns of beta-blockers appeared overrated, including an increased risk of depression [19] or erectile dysfunction [20], while beta-blockers are now safe and protective in peripheral artery disease [21] and chronic obstructive pulmonary disease [22]. ...
Beta-blockers have solid documentation in preventing cardiovascular complications in the treatment of hypertension; atenolol, metoprolol, oxprenolol and propranolol demonstrate proven cardiovascular prevention in hypertension mega-trials. Hypertension is characterised by activation of the sympathetic nervous system from early to late phases, which makes beta-blockers an appropriate treatment seen from a pathophysiological viewpoint, especially in patients with an elevated heart rate. Beta-blockers represent a heterogenous class of drugs with regard to both pharmacodynamic and pharmacokinetic properties. This position is manifest by reference to another clinical context, beta-blocker treatment of heart failure, where unequivocally there is no class effect (no similar benefit from all beta-blockers); there are good and less good beta-blockers for heart failure. Analogous differences in beta-blocker efficacy is also likely in hypertension. Beta-blockers are widely used for the treatment of diseases comorbid with hypertension, in approximately 50 different concomitant medical conditions that are frequent in patients with hypertension, leading to many de facto beta-blocker first choices in clinical practice. Thus, beta-blockers should be regarded as relevant first choices for hypertension in clinical practice, particularly if characterised by a long half-life, highly selective beta-1 blocking activity and no intrinsic agonist properties.
SUMMARY
Beta-blockers have solid documentation in preventing cardiovascular complications in the treatment of hypertension; atenolol, metoprolol, oxprenolol and propranolol demonstrate proven cardiovascular prevention in hypertension mega-trials
Hypertension is characterised by activation of the sympathetic nervous system from early to late phases, which makes beta-blockers an appropriate treatment seen from a pathophysiological viewpoint, especially in patients with an elevated heart rate
Beta-blockers represent a heterogenous class of drugs with regard to both pharmacodynamic and pharmacokinetic properties
This position is manifest by reference to another clinical context, beta-blocker treatment of heart failure, where unequivocally there is no class effect (no similar benefit from all beta-blockers); there are good and less good beta-blockers for heart failure
Analogous differences in beta-blocker efficacy is also likely in hypertension
Beta-blockers are widely used for the treatment of diseases comorbid with hypertension, in approximately 50 different concomitant medical conditions that are frequent in patients with hypertension, leading to many de facto beta-blockers first choices in clinical practice
These observations, in totality, inform our opinion that beta-blockers are relevant first choices for hypertension in clinical practice and this fact needs highlighting
Further, these arguments suggest European hypertension guideline downgrading of beta-blockers is not justified
... However, other studies in [19]) and nebivolol (vs. metoprolol [20]) have demonstrated effective BP lowering, and no cause for concern regarding worsening of limb ischaemia Glycaemic control Many reports have described a worsening of glycaemic control during treatment with a β-blocker and use of a cardioselective agent helps to minimise these effects [17,18] The clinical significance of this phenomenon may have been overrated, however, worsened glycaemia may be unrelated to β-blockade [21],,and use of a β-blocker in a large diabetes prevention trial was not associated with increased risk of diabetes [22] Bisoprolol or nebivolol has not been associated with worsening of glycaemia [7,[23][24][25][26][27][28][29] Asthma and COPD Bronchospasm in patients with COPD or asthma may be exacerbated by blockade of β 2 -adrenoceptors in the smooth muscle of the airways [30] Non-selective β 1 -blockers, but not β 1 -selective agents, increase the risk of asthma exacerbations [31] A recent (2020) randomised, double-blind, crossover study confirmed that the bronchodilatory effects of bisoprolol were non-inferior during treatment with bisoprolol vs. placebo [32] Such findings have led to a reappraisal of the use of selective β 1 -blockers in patients with asthma or COPD [30,33]; β 1selective agents are no contraindicated in Europe only for "severe bronchial asthma" Erectile function β-blockers, have been associated with new or exacerbated erectile dysfunction [34], although neither bisoprolol nor nebivolol were associated with sexual dysfunction [35][36][37] Nebivolol improved erectile function vs. metoprolol [38,39], or atenolol (± chlorthalidone) [40] Another study demonstrated fewer patients reporting vs. not reporting sexual dysfunction on nebivolol vs. other β-blockers [41], or improved sexual function following a switch to nebivolol [42] This benefit for nebivolol may arise from its additional NO-releasing properties, a mechanism shared with the class of phosphodiesterase-5 inhibitors that are indicated for the management of male erectile dysfunction [43][44][45] human myocardium or cultured cells expressing human β 1 -or β 2 -adrenoceptorsfound that bisoprolol was more β 1selective than nebivolol [49]. An experimental study showed that bisoprolol and xamoterol were about 14-fold selective for the human β 1 -vs. the β 2 -adrenoceptor, compared with lower ratios for atenolol (~ fivefold), acebutolol and metoprolol (~ twofold) [50]. ...
Bisoprolol and nebivolol are highly selective β 1 -adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. Nebivolol has additional vasodilator actions, related to enhanced release of NO in the vascular wall. In principle, this additional mechanism compared with bisoprolol might lead to more potent vasodilatation, which in turn might influence the effectiveness of nebivolol in the management of HFrEF, IHD and hypertension. In this article, we review the therapeutic properties of bisoprolol and nebivolol, as representatives of “second generation” and “third generation” β-blockers, respectively. Although head-to-head trials are largely lacking, there is no clear indication from published studies of an additional effect of nebivolol on clinical outcomes in patients with HFrEF or the magnitude of reductions of BP in patients with hypertension.
... With regards to which β-blocker prefer in PAD patients, the vasodilating, endothelium-dependent, NO-releasing properties of nebivolol might be beneficial in this context. The Nebivolol or Metoprolol in Arterial Occlusive Disease Trial [47] found that both nebivolol and metoprolol in patients with intermittent claudication and arterial hypertension were well tolerated and similar in terms of improvement in maximal walking distance during a treatment period of ≈1 year. However, nebivolol showed an advantage vs. metoprolol with a significant improvement in pain-free walking distance [+34% (p <0.003) vs. +17% for metoprolol (p <0. ...
β-blockers represent a mainstay in the pharmacological approach to patients affected by heart failure with reduced ejection fraction (HFrEF). However, underuse of this class of drugs is still reported, especially in the presence of cardiovascular and non-cardiovascular comorbidities, even if they are not contraindications for prescription of a β-blocker. The prognostic benefit of β-blockers is relevant in the presence of comorbidities, and achievement of the maximum tolerated dose is an important goal to increase their favorable prognostic role. The aim of the present review is to analyze the available evidence on the use of β-blockers in HFrEF patients with the most common comorbidities. In particular, we will discuss the role and most appropriate beta-blocker in patients with pulmonary disease (bisoprolol, metoprolol, nebivolol), diabetes (carvedilol and nebivolol), atrial fibrillation (all indicated for rate control, with metoprolol as the first choice followed by bisoprolol, nebivolol, and carvedilol), erectile dysfunction (bisoprolol and nebivolol), peripheral arterial disease (nebivolol), and other conditions, in order to clarify the correct use of this class of drugs in the clinical practice.
... 3,4 The trials cited to support these recommendations focused on cardiovascular events broadly, or differences in safety and efficacy between different antihypertensive classes, rather than PAD-specific outcomes. [32][33][34][35][36][37][38][39][40] Our MR study provides strong evidence consistent with a casual effect of increased BP on PAD. In the absence of large, randomized trials of antihypertensive medications focused on PAD-specific outcomes, these results add support for current guideline recommendations, and suggest possible medication classes that warrant further study specifically for PAD. ...
Objective
We aimed to estimate the effect of blood pressure (BP) traits and BP-lowering medications (via genetic proxies) on peripheral artery disease.
Approach and Results
Genome-wide association studies summary statistics were obtained for BP, peripheral artery disease (PAD), and coronary artery disease. Causal effects of BP on PAD were estimated by 2-sample Mendelian randomization using a range of pleiotropy-robust methods. Increased systolic BP (SBP), diastolic BP, mean arterial pressure (MAP), and pulse pressure each significantly increased risk of PAD (SBP odds ratio [OR], 1.20 [1.16–1.25] per 10 mm Hg increase, P =1×10 ⁻²⁴ ; diastolic BP OR, 1.27 [1.18–1.35], P =4×10 ⁻ ¹¹ ; MAP OR, 1.26 [1.19–1.33], P =6×10 ⁻ ¹⁶ ; pulse pressure OR, 1.31 [1.24–1.39], P =9×10 ⁻ ²³ ). The effects of SBP, diastolic BP, and MAP were greater for coronary artery disease than PAD (SBP ratio of Ors, 1.06 [1.0–1.12], P = 0.04; MAP ratio of OR, 1.15 [1.06–1.26], P =8.6×10 ⁻ ⁴ ; diastolic BP ratio of OR, 1.21 [1.08–1.35], P =6.9×10 ⁻ ⁴ ). Considered jointly, both pulse pressure and MAP directly increased risk of PAD (pulse pressure OR, 1.26 [1.17–1.35], P =3×10 ⁻ ¹⁰ ; MAP OR, 1.14 [1.06–1.23], P =2×10 ⁻ ⁴ ). The effects of antihypertensive medications were estimated using genetic instruments. SBP-lowering via β-blocker (OR, 0.74 per 10 mm Hg decrease in SBP [95% CI, 0.65–0.84]; P =5×10 ⁻ ⁶ ), loop diuretic (OR, 0.66 [0.48–0.91], P =0.01), and thiazide diuretic (OR, 0.57 [0.41–0.79], P =6×10 ⁻ ⁴ ) associated variants were protective of PAD.
Conclusions
Higher BP is likely to cause PAD. BP-lowering through β blockers, loop diuretics, and thiazide diuretics (as proxied by genetic variants) was associated with decreased risk of PAD. Future study is needed to clarify the specific mechanisms by which BP influences PAD.
... Secondly, diabetes has been also crucial disease in the world, frequently associated with high blood pressure. For patients with type1 and 2 diabetes mellitus (T1DM and T2DM), hypertension has been a very common complication [10,11]. To continue good BP control can bring effect for reducing the macrovascular and microvascular complications [12,13]. ...
Currently, major categories of antihypertensive agents include diuretics, beta-blockers, calcium channel blockers (CCBs), renin-angiotensin system (RAS) inhibitors [angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB)]. Among them, RAS (ACE inhibitors and ARB) would be recommended to be a first-line treatment when providing antihypertensive agents for hypertensive patients with diabetes, cardiovascular disease, and impaired renal function. Randomized controlled trials (RCT) of RAS inhibitors compared with other antihypertensive showed a rather lower relative risk (RR). They are all-cause death (RR – 0.95), cardiovascular death (RR – 0.84), incidence of cardiovascular disease (RR – 0.93), and incidence of renal dysfunction (RR – 0.91).
... Терапия бета-адреноблокаторами хорошо переносилась пациентами с перемежающейся хромотой и артериальной гипертензией в течение периода лечения около 1 года. В прямом сравнении не было значимой разницы между небивололом и метопрололом [10]. ...
Cardiovascular diseases (CVDs) are the number 1 cause of death globally. Risk factors for CVDs may trigger the development of pathological conditions to a certain degree. The cardiovascular continuum is a continuous chain of interconnected changes in the cardiovascular system from exposure to risk factors via the gradual onset and progression of CVD to the development of terminal heart damage and death. The continuous chain of interconnected changes in the structure and function of several body organs and systems at once within the continuum suggests the presence of common pathophysiological processes, mechanisms of development and progression of organ damages. The drug’s ability to affect all stages of the cardiovascular continuum defines the choice of modern pharmacotherapy for cardiological patients. Using drugs with multi-target (multi-purpose) action is one of the possibilities for optimizing pharmacotherapy. The provided results of clinical studies show that drugs meeting this requirement include ACE inhibitors (ramipril), beta-blockers (metoprolol), lipid-lowering drugs (combination drug rosuvastatin/ezetimib), allopurinol. The choice of drugs for pharmacotherapy of patients with cardiovascular diseases should be based on the presence and severity of all risk factors and associated conditions and taking into account the individual characteristics of the drugs. Patients with chronic heart disease usually need lifelong therapy, and search for the best individual treatment for each patient is crucial. Using drugs with multi-target (multi-purpose) action is one of the possibilities for optimizing treatment.
... Nebivolol was also hailed as a beta-adrenolytic drug with additional vasodilatory action [1], but the evidence of the potential superiority of vasodilatory beta-adrenolytics over the conventional beta-adrenalitis in patients with LEAD is very limited. Metoprolol and nebivolol were compared in a double-blind randomized clinical trial with 128 adrenolytic treatment-naïve patients suffering from intermittent claudication and arterial hypertension [71]. After 48 weeks of treatment, both drugs were found to be well-tolerated, exercising similar hypotensive effect and improving the maximum walking distance and ABI in both groups, without significant differences between the groups. ...
Peripheral artery disease (PAD) is a common disease, though not very well known and often diagnosed on a very late stage, causing not only typical complications such as intermittent claudication, critical limb ischemia or amputations, but also to cardiovascular mortality. The risk of cardiovascular death can be even 11 times higher in patients with symptomatic PAD than in healthy patients. The risk of heart attack, stroke or cardiovascular death is even higher, reaching almost 4% within one year, nearly equal to the risk for patients with coronary artery disease (CAD). In those patients, the 5-year mortality risk is estimated at 10–15%, with cardiovascular disorders being the most likely cause of death. In patients with critical limb ischemia, the risk of cardiovascular death within one year can be as high as 25% and the risk of amputation — 30%. It is estimated that the global population of patients with PAD is over 120 million. The incidence of the diseases is 3–10%, but in patients aged 70 and more, the incidence increases to 14–29%. In Poland, around 4,000 people are hospitalized every year for PAD of lower limbs. The number of PAD-related amputations is over 9,000 per year. Although the methods of PAD diagnosis (e.g. ABI) are often easy and non-invasive, they are scarcely used in clinical practice. Also, optimal conservative management in the form of quitting smoking, modifying the cardiovascular risk factors and supervised exercise is often overlooked. PAD is a major issue not only for vascular surgery, but also for many other medical specializations, including angiology, general medicine, cardiology, or diabetology. As a result of long waiting times for the next visit and lack of access to patient programmes and reimbursed drugs, patients with PAD often report to the doctor when their condition is very serious. Despite the 2017 ESC guidelines on the diagnosis and treatment of peripheral artery disease, prepared together with ESVS, not all healthcare professionals have access to the latest knowledge on PAD diagnosis and treatment. Unfortunately, though published recently, the ESC’s guidelines do not include some of the recent studies, among them the possibly breakthrough COMPASS trial which has the potential to change the paradigm of management of patients with PAD. We must bear in mind that the population with PAD is a difficult patient group who need new treatment methods and optimization of the existing ones in order to visibly improve diagnosis, treatment and prognosis.
... Hypertension is common among patients with both type 1 and 2 diabetes [1,2]. Controlling blood pressure has been demonstrated to be effective for lowering the risk of microvascular (renal, ocular, or neural) and macrovascular (atherosclerotic cardiovascular disease) complications in patients with diabetes [3][4][5]. ...
Renin–angiotensin system (RAS) inhibitors are often used as a first-line treatment for hypertensive patients with diabetes because of purported benefits, such as reno-protection. However, there is no clear evidence for the superiority of RAS inhibitors to other classes of antihypertensives for clinically important outcomes in this population. We conducted a meta-analysis to assess whether RAS inhibitors are better than other classes of antihypertensives for reducing mortality, and cardiovascular and renal events in hypertensive patients with diabetes. From June to December 2017, we searched Medline, Cochrane Library, and the database of the Japan Medical Abstracts Society (ICHUSHI) for relevant published randomized controlled trials that directly compared the effects of RAS inhibitors to other classes of antihypertensives as first-line treatments for reducing adverse outcomes among hypertensive patients with diabetes. Our predetermined outcomes included all-cause death, cardiovascular death, incidence of cardiovascular disease, and renal dysfunction. We identified 16 trials, including a total of 35,052 patients. No significant benefits for RAS inhibitors were found compared to other classes of antihypertensives for all-cause death (relative risk (RR) 0.95, 95% confidence interval (CI) 0.85–1.05, p = 0.29), cardiovascular death (RR 0.84, 95% CI 0.68–1.04, p = 0.11), incidence of cardiovascular disease (RR 0.93, 95% CI 0.84–1.03, p = 0.16), and incidence of renal dysfunction (RR 0.91, 95% CI 0.77–1.06, p = 0.22). In conclusion, RAS inhibitors are not superior to other classes of antihypertensive drugs for reducing all-cause and cardiovascular mortalities, cardiovascular events, and renal events in hypertensive patients with diabetes.
... Studies have shown that beta-blockers, in particular nebivolol, are safe in patients with IC without negative effects on WD. 49 Metoprolol and nebivolol have been compared in a double-blind RCT including 128 beta-blocker-naive patients with IC and hypertension. 265 After a 48week treatment period, both drugs were well tolerated and decreased BP equally. In both groups, maximal WD improved significantly. ...
... V porovnávacej štúdii u pacientov s klaudikačnými bolesťami a esenciálnou hypertenziou pri použití nebivololu 5 mg a metoprololu 100 mg v priebehu 48 týždňov došlo k signifikantému predĺženiu klaudikačného intervalu i vzostupu ABI oproti vstupnému vyšetreniu u oboch skupín. V skupine s nebivololom bolo preukázané významné predĺženie času do vzniku iniciálnej klaudikácie oproti metoprolovej skupine (44). ...
Efektívne ovplyvnenie celkového kardiovaskulárneho (KV) rizika u pacientov s periférnym artériovým ochorením dolných končatín (PAD) je často v klinickej praxi podceňované napriek významnému zvýšeniu kardio-cerebro-vaskulárnej morbidity a mortality. Zákaz fajčenia, dlhodobo dobrá metabolická kontrola diabetu, kontrola tlaku krvi, zdravý životný štýl a liečba pohybom sú dôležité piliere konzervatívnej liečby. Pacienti s PAD majú veľmi vysoké KV riziko, preto je u nich žiaduce dosiahnuť cieľovú hladinu LDL cholesterolu pod 1,8 mmol/l a podľa najnovších poznatkov aj menej. Nemožno zabúdať na modifikáciu životného štýlu hlavne pri redukcii remnantných lipoproteínov, ktoré majú význam práve v periférnej cirkulácii. Na ovplyvnenie globálneho KV rizika je esenciálna liečba ACE-inhibítormi, statínmi a protidoštičkovou liečbou s preferenciou klopidogrelu podľa ostatných odporúčaní ESC/ESVS u symptomatických pacientov s PAD. Kľúčové slová: artériová hypertenzia, rizikové faktory, kardiovaskulárne riziko, periférne artériové ochorenie dolných končatín Peripheral arterial disease of lower extremity and global cardiovascular risk Effective cardiovascular risk treatment is underestimated in clinical practice despite significantly increased cardio-cerebro-vascular mortality and morbidity in Peripheral Arterial Disease of Lower Extremity (PAD) patients. Smoking cessation, longlasting good metabolic diabetes mellitus control, effective blood pressure control, healthy lifestyle and physical activity are important tools in conservative treatment. PAD patients have very high CV risk and the goal level of LDL cholesterol is less than 1,8 mmol/l or even lower according to new studies. What cannot be forgotten is modification of lifestyle especially in reduction of remnant lipoproteins, which play an important role in peripheral circulation. ACE-inhibitors, statins, antiplatelet therapy with preference of clopidogrel in symptomatic PAD patients are essential for global CV risk control according last ESC/ESVS guidelines. Key words: arterial hypertension, risk factors, cardiovascular risk, peripheral arterial disease of lower extremity Vask. med., 2018,10(1):XX-XX Úvod Periférne artériové ochorenie (PAO) je širší pojem, ktorý zahŕňa po-stihnutie viacerých tepnových riečísk okrem postihnutia koronárnych tepien a aorty (obrázok 1). Periférne artériové ochorenie dolných končatín (PAO DK) je len jednou z možných manifestácií PAO. Starší názov ischemická choro-ba dolných končatín (ICHDK) označuje len obliterujúce postihnutie tepnového systému dolných končatín prejavujú-ce sa ischémiou, nie asymptomatické štádiá (1). V najnovších odporúčaniach Európskej kardiologickej spoločnosti (ESC) v spolupráci s Európskou spoloč-nosťou cievnej chirurgie (ESVS) z roku 2017 pre diagnostiku a liečbu perifér-nych artériových chorôb sa objavuje ter-mín "lower extremities arterial disease (LEAD)-choroba tepien dolných kon-čatín" (2). Periférne artériové ochorenie dolných končatín označujeme v tejto práci skratkou PAD. Pokiaľ v roku 2000 bolo na svete približne 164 miliónov chorých s PAD, v roku 2010 to už bolo vyše 202 miliónov. Nárast prevalencie bol globálne takmer 24 %, čo súvisí aj so zlepšením diagnos-tiky choroby (3). V Európe to bolo vyše 40,5 milióna pacientov s PAD. Prvé úda-je o výskyte PAD na Slovensku sa zistili v epidemiologickom prieskume PAOS na základe merania členkovo-ramenové-ho indexu (ABI) praktickými lekármi na vzorke 2 202 pacientov. Hodnotu menej ako 0,9 aspoň na jednej DK malo 9,4 % pacientov s priemerným vekom 72 ro-Obrázok 1. Periférne artériové ochorenie (2) Vysvetlivky: UEAD-upper extremity artery disease-choroby tepien horných končatín, LEAD-lower extremity artery disease-choroby tepien dolných končatín
... Studies have shown that beta-blockers, in particular nebivolol, are safe in patients with IC without negative effects on WD. 49 Metoprolol and nebivolol have been compared in a double-blind RCT including 128 beta-blocker-naive patients with IC and hypertension. 265 After a 48week treatment period, both drugs were well tolerated and decreased BP equally. In both groups, maximal WD improved significantly. ...
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... Studies have shown that beta-blockers, in particular nebivolol, are safe in patients with IC without negative effects on WD. 49 Metoprolol and nebivolol have been compared in a double-blind RCT including 128 betablocker-naive patients with IC and hypertension. 265 and decreased BP equally. In both groups, maximal WD improved significantly. ...
... W przeprowadzonych badaniach wykazano, że beta-adrenolityki, a zwłaszcza nebiwolol, są bezpieczne u pacjentów z chromaniem przestankowym, nie wpływając niekorzystnie na dystans chodu [49]. Metoprolol i nebiwolol porównano w przeprowadzonym metodą podwójnie ślepej próby RCT z udziałem 128 pacjentów z chromaniem przestankowym i nadciśnieniem tętniczym, którzy wcześniej nigdy nie byli leczeni beta-adrenolitykiem [265]. Po 48 tygodniach leczenia oba leki były dobrze tolerowane i spowodowały takie samo obniżenie BP. ...
The сlinical guidelines present the main approaches to the management of patients with arterial hypertension (aH) using the principles of evidence-based medicine. The guidelines include sections containing expanded and updated information on the main aspects of diagnosis, treatment, prevention methods and follow-up patients with hypertension, taking into account the phenotypes of disease and various clinical situations, as well as secondary forms of hypertension of various origins.
Aims: To systematically appraise and summarize the available evidence from published randomized controlled trials considering the effect of nebivolol on blood pressure in patients with hypertension.
Methods: Literature search was performed through Medline (via PubMed), Cochrane Library and Scopus until December 15, 2023. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis.
Results: In total, 7,737 participants with hypertension, who were treated with nebivolol, were analyzed across 91 RCTs. Nebivolol was associated with significantly greater reduction in office systolic and diastolic BP compared to placebo (MD = - 6.01 mmHg; 95% CI = [- 7.46, - 4.55] and MD = - 5.01 mmHg; 95% CI = [- 5.91, - 4.11], respectively). Moreover, resulted a similar reduction in systolic BP (MD = - 0.22 mmHg; 95% CI = [- 0.91, 0.46]) and a significantly greater reduction in diastolic BP compared to the active comparator (MD = - 0.71 mmHg; 95% CI = [- 1.27, - 0.16]). When considering the effect of nebivolol on 24-hour ambulatory BP, notable reductions were observed compared to placebo. In contrast, compared to the active comparators, there was no significant difference in systolic BP reduction, but a significant reduction in diastolic BP favoring nebivolol. Based on moderator analyses, the impact of nebivolol on the pooled estimates remained independent of the dose of nebivolol, age, male sex, trial duration, body mass index (BMI), baseline diabetes, heart failure, and baseline systolic and diastolic BP.
Conclusion: Nebivolol, compared to placebo, showed a significant BP reduction and was non-inferior to other active comparators in terms of BP reduction.
AIM
The “2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease” provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia).
METHODS
A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate.
STRUCTURE
Recommendations from the “2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease” have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.
Background
Besides being commonly used to treat high blood pressure, beta blockers are a family of drugs that are primarily used to regulate irregular cardiac rhythms. Nebivolol is a third generation of beta blockers, which is highly cardioselective, about three times as selective as bisoprolol. In this study, we aimed to evaluate Nebivolol's effectiveness and safety in comparison to other beta blockers.
Methods
We searched the online databases PubMed, ScienceDirect, and Cochrane Library for relevant RCTs evaluating Nebivolol's effect on hypertension management. Relative risk (WRR) and weighted mean difference (WMD), with a 95% confidence interval (CI) were utilized to quantify the impact of nebivolol medication in the treatment of hypertension using a random effects model.
Results
Twelve RCTs are included in the study, the patient numbers in every attempt ranged from 42-273 and 1456 patients in all were included in this review. Nebivolol does not significantly reduce SBP, DBP and HR compared to other beta blockers (WMD −0.57 mmHg, 95% CI [−1.55; 0.42 mmHg] p=0.12; WMD −0.27 mmHg, 95% CI [−1.36; 0.82 mmHg] p=0.63 ; WMD 0.10 BPM, 95% CI [−4.11;1.31 BPM] p=0.96, respectively). Patients treated with Nebivolol has significantly lower LDL-C (WMD -8.88 mg/dL, 95% CI [−15.28; -2.48 mg/dL] p=0.007) and significantly higher HDL-C (WMD 2.30 mg/dL, 95% CI [0.75; 3.84 mg/dL] p=0.004.
Conclusions
According to this study's findings, nebivolol is well tolerated and decreases LDL-C. And higher HDL-C than other beta blocker agents. This review does not recommend nebivolol as first-line treatment in hypertension as Nebivolol does not significantly reduce blood pressure and HR of patients.
Peripheral arterial disease (PAD) is the third leading cause of atherosclerotic morbidity after coronary heart disease and stroke yet is widely underdiagnosed and undertreated. Treatment of risk factors such as diabetes and cigarette smoking can benefit patients with PAD. Patients should have adequate blood pressure and lipid control to decrease clinical manifestations and symptoms of PAD. Use of antithrombotic medications should be individualized to the patient depending on presence of symptoms, revascularization, and comorbidities. All patient care providers, including physicians, pharmacists, nurse practitioners, and physician assistants should incorporate PAD screening in their at-risk patients to improve access for appropriate earlier diagnosis, initiation of guideline directed therapy, and risk factor modification in order to reduce both major adverse CV and limb outcomes. The purpose of this narrative review is to provide an overview of PAD, summarize clinical trial evidence and guideline recommendations for screening and treatment in order to increase awareness among health care providers to ultimately have a positive impact on patient care.
Background: Aging is a key risk factor for atherosclerosis progression that is associated with increased incidence of ischemic events in supplied organs, including stroke, coronary events, limb ischemia, or renal failure. Cardiovascular disease is the leading cause of death and major disability in adults ≥ 75 years of age. Atherosclerotic occlusive disease affects everyday activity, quality of life, and it is associated with reduced life expectancy. As most multicenter randomized trials exclude elderly and very elderly patients, particularly those with severe comorbidities, physical or cognitive dysfunctions, frailty, or residence in a nursing home, there is insufficient data on the management of older patients presenting with atherosclerotic lesions outside coronary territory. This results in serious critical gaps in knowledge and a lack of guidance on the appropriate medical treatment. In addition, due to a variety of severe comorbidities in the elderly, the average daily number of pills taken by octogenarians exceeds nine. Polypharmacy frequently results in drug therapy problems related to interactions, drug toxicity, falls with injury, delirium, and non-adherence. Therefore, we have attempted to gather data on the medical treatment in patients with extra-cardiac atherosclerotic lesions indicating where there is some evidence of the management in elderly patients and where there are gaps in evidence-based medicine. Public PubMed databases were searched to review existing evidence on the effectiveness of lipid-lowering, antithrombotic, and new glucose-lowering medications in patients with extra-cardiac atherosclerotic occlusive disease.
Lower extremity peripheral artery disease (PAD) affects over 230 million adults globally, with hypertension being one of the major risk factors for the development of PAD. Despite the high prevalence, patients with hypertension who have concomitant PAD are less likely to receive adequate therapy. Through this review, we present the current evidence underlying hypertension management in PAD, guideline-directed therapies, and areas pending further investigation. Multiple studies have shown that both high and relatively lower blood pressure levels are associated with worse health outcomes, including increased morbidity and mortality. Hence, guideline-directed recommendation involves cautious management of hypertensive patients with PAD while ensuring hypotension does not occur. Although any antihypertensive medication can be used to treat these patients, the 2017 American Heart Association/American College of Cardiology (AHA/ACC), 2017 European Society of Cardiology (ESC), and 2022 Canadian guidelines favor the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) as the initial choice. Importantly, data on blood pressure targets and treatment of hypertension in PAD are limited and largely stem from sub-group studies and post-hoc analysis. Large randomized trials in patients with PAD are required in the future to delineate hypertension management in this complex patient population.
Document Reviewers
Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).
Purpose of review:
Hypertension (HTN) is a well known risk factor for atherosclerosis and peripheral arterial disease (PAD). PAD affects more than 250 million people globally and is associated with worse clinical outcomes. Although multiple studies have been performed to evaluate treatment of HTN in patients with PAD, blood pressure management in this high-risk cohort remains poor.
Recent findings:
There has been conflicting evidence regarding blood pressure goals in PAD with some recent studies showing adverse outcomes with low blood pressure in this patient population. Current guidelines, however, continue to recommend treatment goals in PAD patients similar to patients without PAD. To date, no single antihypertensive drug class has shown a clear benefit in PAD population over other antihypertensive drug classes.
Summary:
Prospective randomized trials enrolling PAD patients are required that can shed light on optimum blood pressure target and also distinguish between different antihypertensive drugs in terms of reducing adverse outcomes.
Several hypertension guidelines have removed beta-blockers from their previous position as first-choice drugs for the treatment of hypertension. However, this downgrading may not be justified by available evidence because beta-blockers lower blood pressure as effectively as other major antihypertensive drugs and have solid documentation in preventing cardiovascular complications. Suspected inconveniences of beta-blockers such as increased risk of depression or erectile dysfunction may have been overemphasized, while patients with chronic obstructive pulmonary disease or peripheral artery disease, that is, conditions in which their use was previously restricted, will benefit from beta-blocker therapy. Besides, evidence that from early to late phases, hypertension is accompanied by activation of the sympathetic nervous system makes beta-blockers pathophysiologically an appropriate treatment in hypertension. Beta-blockers have favorable effects on a variety of clinical conditions that may coexist with hypertension, making their use either as specific treatment or as co-treatment potentially common in clinical practice. Guidelines typically limit recommendations on specific beta-blocker use to cardiac conditions including angina pectoris, postmyocardial infarction, or heart failure, with little or no mention of the additional cardiovascular or noncardiovascular conditions in which these drugs may be needed or preferred. In the present narrative review, we focus on multiple additional diseases and conditions that may occur and affect patients with hypertension, often more frequently than people without hypertension, and that may favor the choice of beta-blocker. Notwithstanding, beta-blockers represent an in-homogenous group of drugs and choosing beta-blockers with documented effect in prevention and treatment of disease is important for first choice in guidelines.
More than 200 million people worldwide suffer from peripheral arterial occlusive disease (PAOD). As PAOD is a significant risk factor for the occurrence of acute vascular events and, as a result the life expectancy of those affected is also significantly reduced, they are considered high-risk patients. Antithrombotic treatment is one of the most important pharmaceutical cornerstones in the prophylaxis of these events but the effect of acetylsalicylic acid (ASA)-based antithrombocytic monotherapy is limited. There are now indications for the first time that a combination of ASA-based monotherapy with low-dose anticoagulation (rivaroxaban 2 × 2.5 mg) can achieve a significant additional benefit for patients with symptomatic PAOD requiring and not requiring interventions. These new findings have currently been discussed in guidelines and summarized in new recommendations. These results have a significant influence on the peri-interventional and postinterventional antithrombotic treatment of PAOD patients.
The paper considers whether b-adrenoblockers may be used in the therapy of hypertension. It views in more detail the specific features of nebivolol, a third-generation highly selective b-adrenoblocker that has properties of acting on endothelial function and stimulating NO synthesis. The possible mechanism for the angioprotective activity of the drug is described. There is evidence for its antihypertensive efficacy. The effect of nebivolol on target organs in hypertension, its metabolic effects, and the possibilities of using the drug in patients with comorbidities are considered.
Most patients with LEAD are asymptomatic. Walking capacity must be assessed to detect clinically masked LEAD. The clinical signs vary broadly. Atypical symptoms are frequent. Even asymptomatic patients with LEAD are at high risk of CV events and must benefit from most CV preventive strategies, especially strict control of risk factors. Antithrombotic therapies are indicated in patients with symptomatic LEAD. There is no proven benefit for their use in asymptomatic patients. Ankle-brachial index is indicated as first-line test for screening and diagnosis of LEAD. DUS is the first imaging method. Data from anatomical imaging tests should always be analysed in conjunction with symptoms and haemodynamic tests prior to treatment decision. In patients with intermittent claudication, CV prevention and exercise training are the cornerstones of management. If daily life activity is severely compromised, first-line revascularization can be proposed, along with exercise therapy. Chronic limb-threatening ischaemia specifies clinical patterns with a vulnerable limb viability related to several factors. The risk is stratified according to the severity of ischaemia, wounds, and infection. Early recognition of tissue loss and/or infection and referral to the vascular specialist is mandatory for limb salvage by a multidisciplinary approach. Revascularization is indicated whenever feasible. Acute limb ischaemia with neurological deficit mandates urgent revascularization.
We aim to determine whether nebivolol has a better effect on endothelial dysfunction compared with other β-blockers or other classes of antihypertensive drugs. Searches of the PubMed, EMBASE, etc. were performed to analyze all the randomized controlled trials using nebivolol to treat essential hypertension. The primary end points included a measurement of peripheral endothelial function by brachial flow mediated vasodilatation (FMD) or forearm blood flow (FBF). A random-effect model was used to perform the meta-analysis when the studies showed significant heterogeneity, otherwise a descriptive analysis was conducted. Ten studies (689 patients) were included in qualitative analysis and four of which were included in quantitative synthesis. Meta-analysis showed that the changed FMD value before and after treatment with nebivolol was not statistically different from those treated with other β-blockers [Mean difference=1.12, 95% CI (-0.56，2.81), P=0.19]. Descriptive analysis indicated that nebivolol did not have a better endothelium-protective effect than other classes of antihypertensive drugs including olmesartan and perindopril. Nebivolol is not a unique endothelial function-protective agent distinguished from other β-blockers or other classes of antihypertensive drugs. Reversal of endothelial dysfunction is a key point in the prevention and therapy of essential hypertension.
Due to the underlying atherothrombosis, the majority of patients with peripheral arterial occlusive disease (PAOD) have multiple localizations of disease and therefore have a particularly high cardiovascular risk, especially in the perioperative period. Both medicinal secondary prevention and perioperative cardioprotection are of high prognostic importance with respect to cardiovascular events. Myocardial infarction and cardiovascular death are the most common causes for perioperative mortality in vascular surgery patients. The use of secondary preventive and perioperative beta-blockers for reduction of the cardiovascular risk in patients with PAOD has long been a matter of controversial discussion. Recommendations in guidelines are partially contradictory and clinically validated treatment pathways are still lacking. Based on the currently available literature and the valid European and American guidelines, the current evidence on the secondary prophylactic and perioperative use of beta-blocker treatment is illustrated and recommendations are formulated.
The objective of the present guideline is to provide evidence-based, comprehensive and optimal care recommendations for patients with atherosclerotic peripheral artery disease (PAD) of the lower limbs. The guideline is meant to aid medical personnel and patients in making decisions regarding the optimal diagnostic and therapeutic measures for patients with PAD, and to aid with action and decision routes, which may be modified in justified cases. Guidelines established by scientific medical societies are not legally binding for physicians and may thus neither cause liability nor release physicians from liability. What legally constitutes a medical standard in the treatment of a given individual can only be determined individually. The present guideline thus does not relieve physicians from their obligation to individually manage their patients by appraising their patients’ overall situation.
The present guideline aims to compile the most significant evidence and information on the treatment of peripheral arterial disorders from various specialties to offer the reader reliable assistance in everyday practical clinical life.
The review article discusses the use of antihypertensive therapy in patients with arterial hypertension and atherosclerosis of the lower limb arteries from the perspective of current clinical guidelines. Outlined the goal of therapy, rational combination of drugs. The problems and limitations in the appointment of antihypertensive therapy to patients with peripheral arterial diseases in actual clinical practice are discussed. The postulated priority of fixed combinations in the treatment of patients with arterial hypertension and peripheral atherosclerosis to increase adherence to prescribed therapy and improve the prognosis. literature sources from open databases PubMed, MEDLINE, eLibrary are used.
Atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral artery disease, carries a high morbidity and mortality. Risk factor control is especially important for patients with ASCVD to reduce recurrent cardiovascular events. Clinical guidelines have been developed by the Taiwan Society of Cardiology, Taiwan Society of Lipids and Atherosclerosis, and Diabetes Association of Republic of China (Taiwan)to assist health care professionals in Taiwan about the control of hypertension, hypercholesterolemia and diabetes mellitus. This article is to highlight the recommendations about blood pressure, cholesterol, and sugar control for ASCVD. Some medications that are beneficial for ASCVD were also reviewed. We hope the clinical outcomes of ASCVD can be improved in Taiwan through the implementation of these recommendations.
Peripheral arterial disease (PAD) is a global health problem. The risk factors for developing PAD have been clearly described in the literature, as have the medical therapies and preventative strategies for the prevention and treatment of PAD. Unfortunately, PAD patients remain undertreated with regard to guideline-directed medical therapy. During the last 2 decades, endovascular therapies for PAD have evolved such that randomized controlled trial level data are available for the treatment of lower extremity PAD at every major anatomic segment. Furthermore, endovascular therapy has evolved to the point that among experienced operators, an endovascular first strategy is reasonable for the treatment of most patients with intermittent claudication or critical limb ischemia.
The European Society of Cardiology (ESC) guidelines on “Peripheral Arterial Diseases” (PAD) published in 2017 include recommendations on the diagnostics and treatment of atherosclerotic manifestations in peripheral arteries. The guidelines give recommendations for all arterial territories except the aorta and coronary arteries. The following comments are based on the pocket guidelines and focus on the recommendations for secondary prevention of lower extremity arterial disease (LEAD) and carotid artery stenosis. In the recommendations on secondary prevention atherosclerosis is considered as a disease of the whole vascular system. In general, a consistent discontinuance of cardiovascular risk factors is recommended including smoking cessation, statin therapy and control of blood pressure and blood glucose. In all patients with intermittent claudication, supervised exercise training is strongly recommended. A platelet aggregation inhibitor should be given when symptomatic LEAD is present or in the presence of other manifestations of atherosclerosis, such as coronary heart disease (CHD). If activities of daily life are severely compromised revascularization is recommended. If revascularisation is indicated, treatment shold be performed endovascular first on short lesions (e.g. femoro-popliteal <?25?cm). In long vascular occlusions or if the common femoral artery is involved, vascular surgery is indicated if the risk of an operation is justifiable. Despite a lack of data dual antiplatelet therapy is recommended for at least 1 month after endovascular revascularization. In patients with symptomatic stenosis of the internal carotid artery and low periprocedural risk, early revascularization is recommended if the degree of stenosis is more than 50%. In asymptomatic patients with carotid artery stenosis, revascularization should only be carried out if additional factors indicating an increased risk of stroke are present. Antiplatelet therapy is recommended in patients with a carotid artery stenosis of at least 50% and low bleeding risk. In general, a multidisciplinary treatment by a team of vascular specialists is recommended to make decisions for the management of patients with peripheral arterial diseases. © 2018 Deutsche Gesellschaft für Kardiologie - Herz- und Kreislaufforschung e.V. Published by Springer Medizin Verlag GmbH, ein Teil von Springer Nature - all rights reserved
To evaluate the efficacy of pharmacological interventions in improving walking capacity and health-related quality of life for people with intermittent claudication. DATASOURCES: We searched Medline, EMBASE, Cochrane library and relevant websites for studies published from the start of the databases to February 2009. In addition, reference lists were manually searched.
Based upon a power calculation, only robust (n>56), peer-reviewed, double-blinded, randomised and placebo-controlled trials were included. The main outcomes evaluated were maximal walking distance (MWD) and pain-free walking distance on a treadmill. Random models were used in the statistical analysis, and chi-square test were used to test for heterogeneity.
Among 220 trials, only 43 trials fulfilled the quality criteria. Treatment periods, follow-up and treadmill protocols varied substantially. Vasodilator agents and phosphodiesterase inhibitors show robust significant results compared to placebo, but the improvements in MWD are modest. The highest benefit was caused by lipid-lowering agents, which in mean gained above 160 m in MWD, while the other agents only improved MWD about 50 m.
Several drugs have shown to improve MWD, but with limited benefits. Statins seem to be the most efficient drug at the moment.
To quantify the potential harm of beta blockers in patients with peripheral arterial disease.
All randomised controlled trials (RCTs) comparing beta blockers with placebo for the outcomes of claudication and maximal walking distance and time, calf blood flow, vascular resistance and skin temperature were searched using the Cochrane Controlled Trials Register, PubMed and CINAHL. Trials comparing different types of beta blockers were excluded.
Six RCTs fulfilling the above criteria, with a total of 119 patients, were included. The beta blockers studied were atenolol, propranolol, pindolol and metoprolol. None of the trials showed a statistically significant worsening effect of beta blockers on the outcomes measured. There were no reports of any adverse events with the beta blockers studied.
Currently, there is no evidence to suggest that beta blockers adversely affect walking distance in people with intermittent claudication. Beta blockers should be used with caution if clinically indicated, especially in patients with critical ischaemia where acute lowering of blood pressure is contraindicated.
The incidence of peripheral arterial disease (PAD) is on the increase and is associated with a major health concern in current practical care. The most common disease process underlying PAD is atherosclerosis. Atherosclerosis is a complex generalized disease affecting several arterial beds, including the peripheral and coronary circulation. Especially in patients with PAD, high incidences of coronary artery disease (CAD) have been observed, which may be asymptomatic or symptomatic. The prognosis of patients with PAD is related to the presence and extent of underlying CAD. In patients with PAD undergoing major vascular surgery, cardiac complications are the major cause of perioperative morbidity and mortality and indicate a high-risk for adverse long-term cardiac outcome. In order to improve outcome for PAD patients, assessment and aggressive therapy of atherosclerotic risk factors and usage of cardio-protective medications is recommended. Unfortunately, substantial differences in risk factor management and treatment and long-term outcome have been reported between PAD and CAD patients.
To determine the effects of the beta 1 selective adrenoceptor blocker atenolol, the dihydropyridine calcium antagonist nifedipine, and the combination of atenolol plus nifedipine on objective and subjective measures of walking performance and foot temperature in patients with intermittent claudication.
Randomised controlled double blind four way crossover trial.
Royal Hallamshire Hospital, Sheffield.
49 patients (40 men) aged 39-70 with chronic stable intermittent claudication.
Atenolol 50 mg twice daily; slow release nifedipine 20 mg twice daily; atenolol 50 mg plus slow release nifedipine 20 mg twice daily; placebo. Each treatment was given for four weeks with no washout interval between treatments.
Claudication and walking distances on treadmill; skin temperature of feet as measured by thermistor and probe; blood pressure before and after exercise; subjective assessments of walking difficulty and foot coldness with visual analogue scales.
Atenolol did not significantly alter claudication distance (mean change -6%; 95% confidence interval 1% to -13%), walking distance (-2%; 4% to -8%), or foot temperature. Nifedipine did not alter claudication distance (-4%; 3% to -11%), walking distance (-4%; 3% to -10%), or foot temperature. Atenolol plus nifedipine did not alter claudication distance but significantly reduced walking distance (-9%; -3% to -15% (p less than 0.003)) and skin temperature of the more affected foot (-1.1 degrees C; 0 to -2.2 degrees C (p = 0.05)). These effects on walking distance and foot temperature seemed unrelated to blood pressure changes.
There was no evidence of adverse or beneficial effects of atenolol or nifedipine, when given singly, on peripheral vascular disease. The combined treatment, however, affected walking ability and foot temperature adversely. This may have been due to beta blockade plus reduced vascular resistance, which might also explain the reported adverse effects of pindolol and labetalol on claudication.
To assess the age- and sex-specific prevalence of peripheral arterial disease (PAD) and intermittent claudication (IC) in an elderly population, we performed a population-based study in 7715 subjects (40% men, 60% women) aged 55 years and over. The presence of PAD and IC was determined by measuring the ankle-arm systolic blood pressure index (AAI) and by means of the World Health Organization/Rose questionnaire, respectively. PAD was considered present when the AAI was <0.90 in either leg. The prevalence of PAD was 19.1% (95% confidence interval, 18.1% to 20.0%): 16.9% in men and 20.5% in women. Symptoms of IC were reported by 1.6% (95% confidence interval, 1.3% to 1.9%) of the study population (2.2% in men, 1.2% in women). Of those with PAD, 6.3% reported symptoms of IC (8.7% in men, 4.9% in women), whereas in 68.9% of those with IC an AAI below 0.90 was found. Subjects with an AAI <0.90 were more likely to be smokers, to have hypertension, and to have symptomatic or asymptomatic cardiovascular disease compared with subjects with an AAI of 0.90 or higher. The authors conclude that the prevalence of PAD in the elderly is high whereas the prevalence of IC is rather low, although both prevalences clearly increase with advancing age. The vast majority of PAD patients reports no symptoms of IC.
Cardiovascular complications are the most important causes of perioperative morbidity and mortality among patients undergoing major vascular surgery.
We performed a randomized, multicenter trial to assess the effect of perioperative blockade of beta-adrenergic receptors on the incidence of death from cardiac causes and nonfatal myocardial infarction within 30 days after major vascular surgery in patients at high risk for these events. High-risk patients were identified by the presence of both clinical risk factors and positive results on dobutamine echocardiography. Eligible patients were randomly assigned to receive standard perioperative care or standard care plus perioperative beta-blockade with bisoprolol.
A total of 1351 patients were screened, and 846 were found to have one or more cardiac risk factors. Of these 846 patients, 173 had positive results on dobutamine echocardiography. Fifty-nine patients were randomly assigned to receive bisoprolol, and 53 to receive standard care. Fifty-three patients were excluded from randomization because they were already taking a beta-blocker, and eight were excluded because they had extensive wall-motion abnormalities either at rest or during stress testing. Two patients in the bisoprolol group died of cardiac causes (3.4 percent), as compared with nine patients in the standard-care group (17 percent, P=0.02). Nonfatal myocardial infarction occurred in nine patients given standard care only (17 percent) and in none of those given standard care plus bisoprolol (P<0.001). Thus, the primary study end point of death from cardiac causes or nonfatal myocardial infarction occurred in 2 patients in the bisoprolol group (3.4 percent) and 18 patients in the standard-care group (34 percent, P<0.001).
Bisoprolol reduces the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction in high-risk patients who are undergoing major vascular surgery.
To clarify contradictions in past reports and the package inserts for beta-adrenergic blocking agents (beta-blockers) for patients with intermittent claudication (IC), we investigated the effects of beta-blockers in patients with IC using the systematic review technique. Data sources were randomized, controlled trials that investigated the effects of beta-blockers compared with the placebo or untreated group (controls) in patients with IC. Primary endpoints were walking distance and walking time, and secondary endpoints were ankle-brachial index (ABI) and calf blood flow. Nine trials were included in the analysis. Meta-analysis showed that there was a significant worsening in maximal walking distance and initial claudication distance in patients receiving beta-blockers, with standardized mean differences of -0.31 and -0.39 (95% confidence interval -0.58 to -0.04 and -0.73 to -0.06, P=0.03 and 0.02, respectively) compared with controls. There were no significant differences in maximal walking time (0.07, -0.24 to 0.37), time to onset of claudication (0.12, -0.23 to 0.47), ABI at rest (0.24, -0.30 to 0.78), calf blood flow at rest (0.00, -0.26 to 0.25), and calf blood flow after exercise (-0.23, -0.69 to 0.22). However, only one trial evaluated ABI, and the number of cases is increasing, suggesting that beta-blockers do not worsen ABI. There was no evidence that beta-blockers prescribed for patients with IC have unsuitable "precautions" in the package inserts. However, reluctance to administer beta-blockers to patients because they have IC is not appropriate.
The relative importance of hypertension as a risk factor for peripheral vascular disease is of the same order as coronary artery disease. The design of drug studies in occlusive vascular disease presents several problems. First, investigations must be placebo-controlled and crossover in design. Second, since these patients are very much at risk from other vascular occlusions, length of treatment phase is critical. Third, drug doses are also critical-probably best chosen by titration to similar anti-hypertensive effect. Fourth, patients must be trained in treadmill procedure. Fifth, measurements of limb blood flow must be accompanied where possible by "functional" assessment, e.g., claudication distance. With respect to the specific problem of low perfusion pressure distal to the blockage of peripheral vasculature, resting blood flow may remain normal, implying compensatory reduction in tone of arteriolar resistance vessels. Thus, regional circulation distal to blockage is sensitive to changes in perfusion pressure. There is the risk of "steal" with vasodilator agents; however, conflict exists in the literature over effects of [beta]-blockers in this situation. In view of its peripheral hemodynamic profile, the theoretical possibilities with the [beta]-blocker/vasodilator carvedilol in patients with hypertension and peripheral vascular disease seem extremely rewarding, but remain to be borne out in practice.
β-Adrenergic blockers have been considered relatively contraindicated in peripheral arterial disease because of the perceived risk that these drugs could worsen intermittent claudication. Therefore, we conducted a meta-analysis of available randomized controlled trials from the English-language literature to determine whether or not β-blockers exacerbate intermittent claudication. The primary focus of this analysis was the effect of β-blockers on exercise dura tion, measured as walking capacity or endurance time. Outcomes were pooled where appropriate. Of 11 eligible reports, six included 11 individual controlled treatment comparisons that provided data for an analysis of pain-free exercise capacity; no effect size was statistically significant. The pooled effect size for pain-free walking distance was -0.24 (95% confidence interval, -0.62 to 0.14), indicat ing no significant impairment of walking capacity compared with placebo. Only one study reported that certain β-blockers were associated with worsening of intermittent claudication. These results strongly suggest that β-blockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild to moderate peripheral arterial disease. In the absence of other con traindications, β-blockers can probably be used safely in such patients.
(Arch Intern Med. 1991;151:1769-1776)
In a placebo‐controlled double‐blind study 14 hypertensive patients with intermittent claudication were treated with metoprolol (100‐200 mg daily) and methyldopa (500‐1000 mg daily) for 3 weeks and their effects on heart rate, blood pressure as well as on resting and hyperaemic calf blood flow and vascular resistance were compared. In their antihypertensive effect metoprolol and methyldopa did not differ significantly. In 23 diseased limbs the calf blood flow and vascular resistance remained unchanged at rest during the trial. The active drugs reduced hyperaemic flow (P less than 0.05). The peak flow was reduced by 20% (P greater than 0.01) with metoprolol and by 15% with methyldopa below the initial level and by 17% and by 12% below the level recorded on placebo, respectively. Neither of the drugs influenced vascular resistance during reactive hyperaemia. Thus, in patients with intermittent claudication antihypertensives should be used with care.
Figure 1. Mechanisms Underlying Endothelial (Vascular) Dysfunction in Vascular Disease
Although its clinical use in Europe dates almost 10 years, nebivolol is a beta-blocker that has been only recently introduced in the U.S. market. Like carvedilol, nebivolol belongs to the third generation of beta-blockers, which possess direct vasodilator properties in addition to their adrenergic blocking characteristics. Nebivolol has the highest beta(1)-receptor affinity among beta-blockers and, most interestingly, it substantially improves endothelial dysfunction via its strong stimulatory effects on the activity of the endothelial nitric oxide synthase and via its antioxidative properties. Because impaired endothelial activity is attributed a major causal role in the pathophysiology of hypertension, coronary artery disease, and congestive heart failure, the endothelium-agonistic properties of nebivolol suggest that this drug might provide additional benefit beyond beta-receptor blockade. Although lesser beta-blocker-related side effects have been reported in patients with chronic obstructive pulmonary disease or impotence taking nebivolol, side effects and contraindications overlap those of other beta-blockers. Clinically, this compound has been proven to have antihypertensive and anti-ischemic effects as well as beneficial effects on hemodynamics and prognosis in patients with chronic congestive heart failure. Further studies are now necessary to compare the benefit of nebivolol with that of other drugs in the same class and, most importantly, its prognostic impact in patients with hypertension.
Beta (ss) blockers are indicated for use in coronary artery disease (CAD). However, optimal therapy for people with CAD accompanied by intermittent claudication has been controversial due to the presumed peripheral haemodynamic consequences of beta blockers, leading to worsening symptoms of intermittent claudication.
To quantify the potential harm of beta blockers on maximum walking distance, claudication distance, calf blood flow, calf vascular resistance, and skin temperature when used in patients with peripheral arterial disease (PAD).
The Cochrane Peripheral Vascular Diseases (PVD) Group searched for publications describing randomised controlled trials (RCTs) of beta blockers in PAD in their Trials Register (last searched 6 May 2008) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched The Cochrane Library 2008, Issue 2). We handsearched relevant journals and conference proceedings.
Randomised controlled trials evaluating the role of both selective (beta1) and non-selective (beta1 and beta2) beta blockers compared with placebo. We excluded trials comparing different types of beta blockers.
Primary outcome measures were claudication distance in metres, and the time to claudication in minutes, and maximum walking distance in metres and minutes (as assessed by treadmill).Secondary outcome measures were calf blood flow (ml/100 ml/min), calf vascular resistance, and skin temperature (degrees C).
We included six RCTs fulfilling the above criteria, with a total of 119 patients. The beta blockers studied were atenolol, propranolol, pindolol, and metoprolol. None of the trials showed a statistically significant worsening effect of beta blockers on either the primary or secondary outcomes. There were no reports of any adverse events with the beta blockers studied.
There is currently no evidence that beta blockers adversely affect walking distance in people with intermittent claudication. However, due to the lack of large published trials beta blockers should be used with caution if clinically indicated.
An ankle-brachial index (ABI; ratio of ankle and brachial systolic blood pressure) <0.9 indicates peripheral arterial disease (PAD) and is a strong predictor of cardiovascular events. The aim of the present study was to address the prognostic value of different methods of ABI calculation.
In 831 patients admitted with chest pain for diagnostic heart catheterization, blood pressure of both anterior and posterior tibial arteries was measured. ABI was calculated for each leg with the higher of the 2 ankle pressures (current definition of the American Heart Association) or with the lower of the 2 ankle pressures (modified definition) in relation to the higher of the left or right brachial systolic blood pressure. For each patient, the lower ABI from both legs was used for further evaluation. Fifteen patients (1.8%) with ABI >1.5 were excluded. We compared patients with ABI <0.9 according to the current definition (with PAD, n=204 [25.0%]), those with ABI >or=0.9 according to the modified definition (without PAD, n=524 [64.2%]), and those with ABI <0.9 according to the modified definition and >or=0.9 according to the current definition (suspected PAD, n=88 [10.8%]). Follow-up data (median 6.6 years) were available for 812 patients (99.5%); 157 patients (19.3%) experienced cardiovascular events (cardiovascular death, myocardial infarction, or stroke). Patients without PAD had the lowest cardiovascular event rate, whereas event rates were comparable for patients with PAD and those with suspected PAD (14.8% versus 28.4% versus 25.0%, respectively). In a fully adjusted Cox regression analysis that included patients without PAD as the reference group, the hazard ratio (95% CI) was 1.56 (0.97 to 2.53) for patients with suspected PAD and 1.67 (1.16 to 2.40) for patients with PAD.
When the higher ankle pressure is used for ABI calculation, a group of patients at high risk for cardiovascular events is overlooked. With a simple modification of ABI (use of the lower instead of the higher ankle pressure), more patients at risk could be identified.
The effects of single doses of propranolol and metoprolol on skin temperature and skin and muscle blood flow were compared in 10 normal subjects and four patients with essential hypertension. In normal subjects the mean skin temperature fell by 1.30 +/- 0.62 degrees C 90 minutes after 80 mg propranolol and 0.15 +/- 0.05 degrees C after 100 mg metoprolol. Skin blood flow and resting muscle blood flow were not affected by metoprolol but fell significantly after propranolol. Both drugs reduced post-exercise muscle hyperaemia, propranolol by more than metoprolol. Similar changes were seen in the hypertensive patients. Propranolol should be used with care in patients with known vascular disease.
Beta-Adrenergic blockers have been considered relatively contraindicated in peripheral arterial disease because of the perceived risk that these drugs could worsen intermittent claudication. Therefore, we conducted a meta-analysis of available randomized controlled trials from the English-language literature to determine whether or not beta-blockers exacerbate intermittent claudication. The primary focus of this analysis was the effect of beta-blockers on exercise duration, measured as walking capacity or endurance time. Outcomes were pooled where appropriate. Of 11 eligible reports, six included 11 individual controlled treatment comparisons that provided data for an analysis of pain-free exercise capacity; no effect size was statistically significant. The pooled effect size for pain-free walking distance was -0.24 (95% confidence interval, -0.62 to 0.14), indicating no significant impairment of walking capacity compared with placebo. Only one study reported that certain beta-blockers were associated with worsening of intermittent claudication. These results strongly suggest that beta-blockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild to moderate peripheral arterial disease. In the absence of other contraindications, beta-blockers can probably be used safely in such patients.
The relative importance of hypertension as a risk factor for peripheral vascular disease is of the same order as coronary artery disease. The design of drug studies in occlusive vascular disease presents several problems. First, investigations must be placebo-controlled and crossover in design. Second, since these patients are very much at risk from other vascular occlusions, length of treatment phase is critical. Third, drug doses are also critical--probably best chosen by titration to similar antihypertensive effect. Fourth, patients must be trained in treadmill procedure. Fifth, measurements of limb blood flow must be accompanied where possible by "functional" assessment, e.g., claudication distance. With respect to the specific problem of low perfusion pressure distal to the blockage of peripheral vasculature, resting blood flow may remain normal, implying compensatory reduction in tone of arteriolar resistance vessels. Thus, regional circulation distal to blockage is sensitive to changes in perfusion pressure. There is the risk of "steal" with vasodilator agents; however, conflict exists in the literature over effects of beta-blockers in this situation. In view of its peripheral hemodynamic profile, the theoretical possibilities with the beta-blocker/vasodilator carvedilol in patients with hypertension and peripheral vascular disease seem extremely rewarding, but remain to be borne out in practice.
Previous investigators have observed a doubling of the mortality rate among patients with intermittent claudication, and we have reported a fourfold increase in the overall mortality rate among subjects with large-vessel peripheral arterial disease, as diagnosed by noninvasive testing. In this study, we investigated the association of large-vessel peripheral arterial disease with rates of mortality from all cardiovascular diseases and from coronary heart disease.
We examined 565 men and women (average age, 66 years) for the presence of large-vessel peripheral arterial disease by means of two noninvasive techniques--measurement of segmental blood pressure and determination of flow velocity by Doppler ultrasound. We identified 67 subjects with the disease (11.9 percent), whom we followed prospectively for 10 years.
Twenty-one of the 34 men (61.8 percent) and 11 of the 33 women (33.3 percent) with large-vessel peripheral arterial disease died during follow-up, as compared with 31 of the 183 men (16.9 percent) and 26 of the 225 women (11.6 percent) without evidence of peripheral arterial disease. After multivariate adjustment for age, sex, and other risk factors for cardiovascular disease, the relative risk of dying among subjects with large-vessel peripheral arterial disease as compared with those with no evidence of such disease was 3.1 (95 percent confidence interval, 1.9 to 4.9) for deaths from all causes, 5.9 (95 percent confidence interval, 3.0 to 11.4) for all deaths from cardiovascular disease, and 6.6 (95 percent confidence interval, 2.9 to 14.9) for deaths from coronary heart disease. The relative risk of death from causes other than cardiovascular disease was not significantly increased among the subjects with large-vessel peripheral arterial disease. After the exclusion of subjects who had a history of cardiovascular disease at base line, the relative risks among those with large-vessel peripheral arterial disease remained significantly elevated. Additional analyses revealed a 15-fold increase in rates of mortality due to cardiovascular disease and coronary heart disease among subjects with large-vessel peripheral arterial disease that was both severe and symptomatic.
Patients with large-vessel peripheral arterial disease have a high risk of death from cardiovascular causes.
Beta-Adrenergic blockers have not been widely used in patients with peripheral vascular disease because these drugs have been reported to worsen the symptoms of intermittent claudication. To test this assumption we studied the effects of a beta 1-selective and a nonselective beta-adrenergic blocker on postexercise calf blood flow and symptoms of claudication in 19 patients with mild-to-moderate peripheral vascular disease. Subjects received placebo for 3 weeks, and then were randomized to 120 mg/day propranolol or 150 mg/day metoprolol with the use of a crossover design. Blood flow in the calf was measured by strain-gauge plethysmography at rest and immediately after exercise on a bicycle ergometer at a low and a high workload. The symptoms of claudication were monitored during bicycle exercise and by patient diaries maintained between visits. Maximal exercise heart rate was reduced an equivalent amount by metoprolol (19 beats/min) and propranolol (16 beats/min). Mean arterial pressure was reduced by propranolol at rest and by both drugs with exercise. Calf blood flow was not affected by either drug compared with placebo at rest or at either workload. In addition, the symptoms of claudication were not worsened by either drug. We conclude that despite evidence of beta 1-adrenergic blockade and a lowering of arterial pressure, neither beta-adrenergic blocker adversely affected the peripheral circulation.
Until recently beta-adrenergic blocking agents were considered contraindicated in peripheral arterial occlusive disease (PAOD). However, in recent years several studies have failed to show negative effects on peripheral blood flow. It was the aim of this study to compare the effects of celiprolol, a beta-1-adrenergic blocking agent with intrinsic sympathomimetic activity (ISA), and of metoprolol, a beta-1-adrenergic blocking agent without ISA, on peripheral blood flow of patients with and without PAOD. In an acute trial 24 patients (group I: 12 patients with PAOD stage I and II; group II: 12 patients without PAOD received a single dose of 200 mg celiprolol or 200 mg metoprolol in a double-blind crossover design. Celiprolol induced no significant changes in calf and skin blood flow at rest or during reactive hyperemia. Basal vascular resistance (BVR) and minimal vascular resistance (MVR) were not affected. Metoprolol, however, significantly reduced muscle blood flow and increased BVR in both groups. Subsequently the patients were treated in a randomized double-blind design with a daily dose of 200 mg celiprolol or metoprolol for three weeks. In long-term treatment skin and muscle blood flow at rest and during reactive hyperemia, BVR, and MVR were not affected by celiprolol. Metoprolol significantly lowered calf blood flow at rest in patients with PAOD; other parameters remained unchanged. In patients without PAOD, metoprolol caused a significant decrease of calf blood flow at rest and an increase of BVR. Calf blood flow during reactive hyperemia, as well as skin blood flow at rest and during reactive hyperemia, showed no significant changes.(ABSTRACT TRUNCATED AT 250 WORDS)
In a six month placebo-controlled cross-over trial twenty patients with hypertension and peripheral arterial disease were randomised to captopril 25 mg twice daily, atenolol 100 mg once daily, labetalol 200 mg twice daily, or pindolol 10 mg twice daily for one month. Although all treatments were equally effective at lowering blood pressure, pain-free and maximum walking distances on a treadmill were decreased by atenolol, labetalol, and pindolol, but not by captopril. Post-exercise calf blood flow availability was impaired by atenolol, labetalol, and pindolol, but not by captopril. Despite ancillary characteristics of cardioselectivity, intrinsic sympathomimetic activity, or combination with alpha-blockade, beta-blockers seem to impair the lower limb circulation in such patients, whereas captopril seems to preserve it, possibly by maintaining the collateral blood supply.
The present study was designed to assess the short-term effects of beta-blocking antihypertensive treatment on leg blood flow in patients with peripheral artery disease. Seven patients with intermittent claudication were randomly allocated to treatment with atenolol 100 mg or pindolol 10 mg. Patients switched therapy after one month of treatment. Venous occlusion plethysmography on the calves was used to assess the effects on leg blood flow after one and two months of treatment. The average 10% reduction of the systolic and diastolic blood pressures was not associated with any reduction of blood flow at rest. There was on average 3.4 ml reduction of peak flow which had no influence on the painfree or total walking distance.
In a placebo-controlled double-blind study 14 hypertensive patients with intermittent claudication were treated with metoprolol (100-200 mg daily) and methyldopa (500-1000 mg daily) for 3 weeks and their effects on heart rate, blood pressure as well as on resting and hyperaemic calf blood flow and vascular resistance were compared. In their antihypertensive effect metoprolol and methyldopa did not differ significantly. In 23 diseased limbs the calf blood flow and vascular resistance remained unchanged at rest during the trial. The active drugs reduced hyperaemic flow (P less than 0.05). The peak flow was reduced by 20% (P greater than 0.01) with metoprolol and by 15% with methyldopa below the initial level and by 17% and by 12% below the level recorded on placebo, respectively. Neither of the drugs influenced vascular resistance during reactive hyperaemia. Thus, in patients with intermittent claudication antihypertensives should be used with care.
Ten patients with chronic intermittent claudication were included in a double-blind, randomized cross-over study of placebo, propranolol 80 mg b.i.d. and metoprolol 100 mg b.i.d., each given for two months. At the end of each treatment period, the patients were tested on a treadmill and the time to first claudication pain and to intolerable claudication pain was noted.
There was no decrease in time to first claudication pain or to intolerable pain with either propranolol or metoprolol as compared to placebo.
Nebivolol, a beta 1 selective adrenergic receptor antagonist with additional properties, is a racemic mixture of (S,R,R,R)- and (R,S,S,S)-enantiomers. We investigated its effects on human forearm vasculature. Blood flow was measured using venous occlusion plethysmography during brachial artery infusion of drugs. Interaction between nebivolol and the L-arginine/nitric oxide pathway was investigated via comparison with carbachol (an endothelium-dependent agonist) and nitroprusside, and by coinfusion of a competitive inhibitor of nitric oxide synthase, NG-monomethyl L-arginine (LNMMA) +/- L-arginine. Nebivolol (354 micrograms/min) increased blood flow by 91 +/- 18% (mean +/- SEM, n = 8, P < .01) whereas an equimolar dose of atenolol had no significant effect. L-NMMA (1 mg/min) inhibited vasodilation to nebivolol (by 65 +/- 10%) and carbachol (by 49 +/- 8%) to a significantly greater extent than it reduced responses to nitroprusside. Inhibition of nebivolol response by L-NMMA was abolished by L-arginine (62 +/- 11% inhibition by L-NMMA, 15 +/- 17% inhibition by L-NMMA with L-arginine, 10 mg/min, n = 8). Vasodilation caused by the (S,R,R,R)- and (R,S,S,S)-enantiomers was similar. We conclude that nebivolol vasodilates human forearm vasculature via the L-arginine/nitric oxide pathway.
Guidelines for the clinical development of drugs in peripheral arterial disease (PAD) have been issued by the Food and Drug Administration for the United States and by the regulatory agency of the European Union for Europe. With increasing globalization, transatlantic cooperation in drug research and development is essential for the future and would be substantially facilitated by the existence of transatlantic guidelines. A conference was held in Basel, Switzerland, in November 1997 to discuss the scientific background of the existing guidelines on the basis of published evidence and the extensive knowledge of clinical investigators and experienced regulators. The meeting was attended by 52 invited experts from the United States and Europe, as well as by representatives from the 2 regulatory authorities. The main conclusions from the meeting are presented and may serve as a reference for the future development of transatlantic guidelines for the evaluation of pharmacotherapy in PAD.
Guidelines for the clinical development of drugs in peripheral arterial disease (PAD) have been issued by the Food and Drug Administration for the United States and by the regulatory agency of the European Union for Europe. With increasing globalization, transatlantic cooperation in drug research and development is essential for the future and would be substantially facilitated by the existence of transatlantic guidelines. A conference was held in Basel, Switzerland, in November 1997 to discuss the scientific background of the existing guidelines on the basis of published evidence and the extensive knowledge of clinical investigators and experienced regulators. The meeting was attended by 52 invited experts from the United States and Europe, as well as by representatives from the 2 regulatory authorities. The main conclusions from the meeting are presented and may serve as a reference for the future development of transatlantic guidelines for the evaluation of pharmacotherapy in PAD.
Beta blockers reduce the incidence of new coronary events in older patients after myocardial infarction.(1-4) Patients with peripheral arterial disease (PAD) are at increased risk for developing coronary events.(5-8) Many physicians have been reluctant to use p blockers in patients with PAD because of concerns that beta blockers will aggravate intermittent claudication. However, a meta-analysis of 11 randomized controlled studies found that beta blockers do not adversely affect walking capacity or the symptoms of intermittent claudication in patients with mild-to-moderate PAD.(9) We report data from an observational study investigating the effect of beta blockers on the incidence of new coronary events in older patients with symptomatic PAD and prior myocardial infarction.
Intermittent claudication (IC) occurs in patients with peripheral occlusive arterial disease and results in leg pain after walking a certain distance - the claudication distance. Until recently, no specific questionnaire has been available to measure quality of life in patients with IC.
To validate the Claudication Scale (CLAU-S) questionnaire in patients in France, the UK, Germany and Belgium.
Patients completed the CLAU-S questionnaire and provided demographic and clinical data. Pooled data were examined for psychometric and structural validity and test-retest reliability. Structural equation modelling (SEM) was used to confirm that the questionnaire was measuring the causal relationships involved in IC in each of the language groups studied.
Cross-sectional and factor analysis confirmed the validity of the questionnaire in the pooled patient population. Item convergent and discriminant coefficients and internal consistency reliability coefficients met or exceeded standard criteria. Principal component analysis confirmed the factorial structure. The underlying causal relationships in IC were identified using SEM and were consistent in all language groups studied.
The CLAU-S questionnaire has undergone validation in English, French, German and Flemish and has a very satisfactory validity in these languages.
Vascular endothelial dysfunction may predict future atherosclerosis. Hence, an antihypertensive agent that reverses endothelial dysfunction and lowers blood pressure might improve the prognosis of patients with hypertension. We hypothesized that nebivolol, a vasodilating beta-blocker, could improve endothelial dysfunction. We tested this hypothesis by comparing the effects of nebivolol and atenolol on endothelial function.
Twelve hypertensive patients with a mean ambulatory blood pressure of 154+/-7/97+/-10 mm Hg were randomized after a 2-week placebo run-in period (baseline) in a double-blind, crossover fashion to 8-week treatment periods with either 5 mg of nebivolol with 2.5 mg of bendrofluazide or 50 mg of atenolol with 2.5 mg of bendrofluazide. Forearm venous occlusion plethysmography and intra-arterial infusions of acetylcholine and N(G)-monomethyl-L-arginine (L-NMMA) were used to assess stimulated and basal endothelium-dependent nitric oxide release, respectively. Sodium nitroprusside was used as an endothelium-independent control. Nebivolol/bendrofluazide and atenolol/bendrofluazide each lowered the clinic blood pressure to the same extent (132+/-7/82+/-6 and 132+/-9/83+/-8 mm Hg, respectively; P<0.001 from baseline). The vasodilatory response to acetylcholine was significantly increased with nebivolol/bendrofluazide (maximum percentage change in forearm blood flow [mean+/-SEM], 435+/-27%, P<0.001) but not with atenolol/bendrofluazide. Similarly, the endothelium-dependent vasoconstrictive response to L-NMMA was significantly improved only with nebivolol treatment (percentage change in forearm blood flow, -54+/-5%; P<0.001). The response to sodium nitroprusside was not different between treatments, suggesting that the endothelium-independent pathway was unaffected.
Nebivolol/bendrofluazide increased both stimulated and basal endothelial nitric oxide release, whereas for the same degree of blood pressure control, atenolol/bendrofluazide had no effect on nitric oxide bioactivity. Thus, nebivolol may offer additional vascular protection in treating hypertension.
It has been reported that administration of low-dose aspirin significantly reduces the frequency of major cardiovascular events in patients with hypertension and coronary artery disease. It is generally considered that the preventative effects of long-term aspirin administration on major cardiovascular events are due to the inhibition of platelet aggregation.
It is not known whether administration of low-dose aspirin restores endothelium-dependent vasodilatation, and this study was undertaken to prove or disprove this question in patients with hypertension.
Flow-mediated endothelium-dependent dilatation and glyceryl trinitrate-induced endothelium-independent dilatation were investigated in 18 hypertensive patients and 10 normotensive control subjects. In the hypertensive patients, flow-mediated dilatation was investigated and cyclic guanosine monophosphate plasma (cGMP) was measured before and at 8 weeks after the administration of 162 mg of aspirin.
Flow-mediated dilatation before aspirin administration was more reduced in the hypertensive patients than in the control subjects (6.4+/-2.0% vs. 11.3+/-2.3%, p <0.0001). Glyceryl trinitrate-induced dilatation before aspirin administration was similar in hypertensive patients and control subjects. Flow-mediated dilatation after aspirin administration was improved compared with that before aspirin administration (10.4+/-3.5% vs. 6.4+/-2.0%, p<0.0004). The cGMP product after aspirin administration was significantly higher than that before aspirin administration.
Administration of low-dose aspirin may restore the endothelium-dependent vasodilatation in hypertensive patients. Furthermore, increased nitric oxide production may play a partial role in the improvement in endothelial function induced by administration of low-dose aspirin.
intermittent claudication (IC) is a common condition that has a major impact on the patients' quality of life (QoL). Generic QoL instruments often lack sensitivity to detect small but clinically significant variation in QoL. Disease-specific instruments may overcome this problem. This study aims to review various disease-specific QoL instruments available for use in IC and make recommendations for clinical utilization based on validity, reliability and responsiveness.
a detailed literature search and extensive bibliography review of all papers relating to disease-specific QoL and IC.
several disease-specific QoL instruments are available for use in patients with IC. The most notable of these are the Claudication Scale (CLAU-S), Sickness Impact Profile - Intermittent Claudication (SIP(IC)) and the VascuQoL. The Walking Impairment Questionnaire (WIQ) is an objective measure of the patient's walking ability and not a QoL instrument.
many of the questionnaires are new and have undergone only a limited validation process. More work is required in this field before any one disease-specific QoL instrument can be recommended for use in patients with IC.
This study was undertaken to investigate the possible negative effect of beta-blockers on skin microcirculation in patients with intermittent claudication and hypertension. Methods and materials In this clinical crossover study, 20 patients with mild to moderate hypertension, treated with long-term beta-blockade, and intermittent claudication or ischemic rest pain, underwent assessment of peripheral circulation before and after 2-week withdrawal of beta-blocking therapy and again 2 weeks after restarting therapy. Replacement therapy (calcium antagonist) was given if considered necessary to control hypertension. Skin microcirculation was assessed with three noninvasive techniques: capillary microscopy of the hallux nailfold, transcutaneous oximetry of the forefoot, and laser Doppler fluxmetry of the great toe.
Mean initial blood pressure was 163/81 mm Hg. Mean heart rate significantly increased with withdrawal of beta-blocker, from 65 bpm to 85 bpm. No significant differences in skin microcirculation and blood pressure were found between measurements obtained before, during, and after withdrawal of beta-blocking therapy. Patients experienced no change in symptoms during the study.
beta-Blockers do not appear to have a negative effect on peripheral skin microcirculation and are therefore not contraindicated to treat hypertension when intermittent claudication or ischemic rest pain is also present.
Endothelial dysfunction plays a key role in atherogenesis. We prospectively investigated the impact of noninvasive measurement of endothelial function on cardiovascular risk in peripheral arterial disease (PAD). The study was specially aimed at assessing whether brachial artery flow-mediated dilation (FMD) added to the predictive value of ankle-brachial pressure index (ABPI).
Of 131 patients monitored for a mean of 23+/-10 months, 18 had a coronary event, 12 a cerebrovascular event, and 9 a peripheral event. The median FMD was lower in patients with an event than in those without (5.8% versus 7.6%, P<0.05), whereas vasodilation to nitroglycerin was similar in the two groups. The cardiovascular event rate was higher in patients with FMD below the median versus those with FMD above the median (P<0.001 by log-rank test). In a Cox proportion hazard model, independent predictors of events were FMD below the median (P<0.01), ABPI below the median (P<0.01), and previous stroke (P<0.02). Similar results were obtained when peripheral events were excluded from the analysis. Below-median ABPI and FMD combined was more accurate in predicting risk (relative risk [RR] 13.0; 95% CI, 3.0 to 56.2; P<0.01) than ABPI (RR, 6.4; 95% CI, 1.4 to 29.1; P<0.02) and FMD (RR, 4.8; 95% CI, 1.1 to 23.3; P<0.05) alone.
A low brachial artery FMD is an independent predictor of cardiovascular risk in patients with PAD and adds to the prognostic value of ABPI, which is currently the most powerful prognostic indicator in PAD.
Among coronary disease patients, concomitant peripheral arterial disease is a potent risk factor for future cardiac events and mortality. We sought to determine clinical and biochemical markers that might better elucidate the relationship between coronary and peripheral arterial disease.
Two months after an index myocardial infarction, 1045 patients provided detailed medical histories and underwent blood testing for selected hemostatic, lipid, and inflammatory markers. Patients were then followed up prospectively for a mean of 26 months.
Compared with individuals without intermittent claudication (n = 966), those with claudication (n = 78) (information was unavailable for 1 individual) were significantly older and demonstrated an increased frequency of diabetes mellitus, tobacco use, prior cardiac and cerebrovascular events, and depressed left ventricular function. Individuals with claudication were less likely to receive beta-blocker therapy after the index infarction. Individuals with claudication had evidence of enhanced procoagulant and proinflammatory states manifested by relative elevations in plasma fibrinogen, D-dimer, C-reactive protein, and serum amyloid A concentrations. During follow-up, the presence of claudication was associated with an independent 2-fold increase in the combined end point of death or nonfatal cardiac event (38.5% vs 17.8%, P =.001) and a 5-fold increase in cardiac mortality (19.2% vs 3.6%, P =.001). Patients with intermittent claudication who were not treated with beta-blockers had a significant 3-fold mortality excess relative to those receiving beta-blockers.
Following myocardial infarction, the added presence of intermittent claudication is associated with heightened procoagulant and proinflammatory states and an underuse of beta-blocker therapy and is a strong independent predictor of recurrent cardiovascular events.
Peripheral arterial disease (PAD) is associated with significant morbidity and mortality and is an important marker of subclinical coronary heart disease. However, estimates of PAD prevalence in the general US population have varied widely.
We analyzed data from 2174 participants aged 40 years and older from the 1999-2000 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial index <0.90 in either leg. The prevalence of PAD among adults aged 40 years and over in the United States was 4.3% (95% CI 3.1% to 5.5%), which corresponds to approximately 5 million individuals (95% CI 4 to 7 million). Among those aged 70 years or over, the prevalence was 14.5% (95% CI 10.8% to 18.2%). In age- and gender-adjusted logistic regression analyses, black race/ethnicity (OR 2.83, 95% CI 1.48 to 5.42) current smoking (OR 4.46, 95% CI 2.25 to 8.84), diabetes (OR 2.71, 95% CI 1.03 to 7.12), hypertension (OR 1.75, 95% CI 0.97 to 3.13), hypercholesterolemia (OR 1.68, 95% CI 1.09 to 2.57), and low kidney function (OR 2.00, 95% CI 1.08 to 3.70) were positively associated with prevalent PAD. More than 95% of persons with PAD had 1 or more cardiovascular disease risk factors. Elevated fibrinogen and C-reactive protein levels were also associated with PAD.
This study provides nationally representative prevalence estimates of PAD in the United States, revealing that PAD affects more than 5 million adults. PAD prevalence increases dramatically with age and disproportionately affects blacks. The vast majority of individuals with PAD have 1 or more cardiovascular disease risk factors that should be targeted for therapy.
We sought to investigate the effect of cardiac medication on long-term mortality in patients with peripheral arterial disease (PAD).
Peripheral arterial disease is associated with increased cardiovascular morbidity and mortality. Treatment guidelines recommend aggressive management of risk factors and lifestyle modifications. However, the potential benefit of cardiac medication in patients with PAD remains ill defined.
In this prospective observational cohort study, 2,420 consecutive patients (age, 64 +/- 11 years, 72% men) with PAD (ankle-brachial index < or =0.90) were screened for clinical risk factors and cardiac medication. Follow-up end point was death from any cause. Propensity scores for statins, beta-blockers, aspirin, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, nitrates, coumarins, and digoxin were calculated. Cox regression models were used to analyze the relation between cardiac medication and long-term mortality.
Medical history included diabetes mellitus in 436 patients (18%), hypercholesterolemia in 581 (24%), smoking in 837 (35%), hypertension in 1,162 (48%), coronary artery disease in 1,065 (44%), and a history of heart failure in 214 (9%). Mean ankle-brachial index was 0.58 (+/-0.18). During a median follow-up of eight years, 1,067 patients (44%) died. After adjustment for risk factors and propensity scores, statins (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.36 to 0.58), beta-blockers (HR 0.68, 95% CI 0.58 to 0.80), aspirins (HR 0.72, 95% CI 0.61 to 0.84), and ACE inhibitors (HR 0.80, 95% CI 0.69 to 0.94) were significantly associated with a reduced risk of long-term mortality.
On the basis of this observational longitudinal study, statins, beta-blockers, aspirins, and ACE inhibitors are associated with a reduction in long-term mortality in patients with PAD.
Clinical studies have demonstrated beneficial effects for clopidogrel in patients with atherothrombotic disease. Recent in vitro studies identified stimulating effects of clopidogrel on endothelial cells, pointing towards mechanisms of action beyond the inhibition of platelet aggregation. We hypothesized that in vivo use of clopidogrel improves endothelial dysfunction in patients with coronary artery disease (CAD). Fifty-eight patients with CAD were randomly assigned to double-blinded oral administration of one single dose of clopidogrel 300 mg (C300) or 600 mg (C600), respectively. Endothelial function was assessed by measurement of flow-mediated dilation (FMD) of the brachial artery before and 2, 4 and 22 h after dose administration, respectively. Inhibition of the platelet ADP P2Y12 receptor by clopidogrel was monitored by the ex vivo analysis of ADP effects on prostaglandin-induced platelet VASP phosphorylation. C600 significantly improved FMD at 2, 4 and 22 h, while C300 significantly improved FMD at 4 and 22 h. Clopidogrel dose- and time-dependently inhibited the platelet ADP P2Y12 receptor without correlation with its stimulatory effects on FMD. Our study demonstrates for the first time in vivo that clopidogrel dose-dependently improves endothelial dysfunction. These results may indicate a new and potentially important aspect of the effect of clopidogrel treatment in patients with CAD.