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Are we misunderstanding β-blockers
Abstract
In myocardial ischaemia and heart failure, beta-blockers with intrinsic sympathomimetic activity (ISA) e.g. pindolol, xamoterol, bucindolol, nebivolol, have performed poorly in reducing morbidity and mortality. In both indications beta-1 blockade is the vital active ingredient. Beta-1 blockade (bisoprolol) is now an alternative first-line choice to Ace-inhibition in the treatment of heart failure. The therapeutic role of beta-blockers in hypertension is less well understood, particularly since the new recommendations in the UK from the NICE committee stating that: 1. beta-blockers are no longer preferred as a routine initial therapy, 2. the combination with diuretics is discouraged due to the risk of induced diabetes, and 3. in younger patients first-choice initial therapy should be an ACE-inhibitor. Recent data from the Framingham Heart Study and other epidemiological studies have indicated that the development of diastolic hypertension in younger subjects is closely linked to weight-increase and an increase in peripheral resistance; such subjects have a high adrenergic drive and cardiac output. In contrast, elderly systolic hypertension mostly arises de novo via poor vascular compliance. Thus in younger, probably overweight, hypertensives (including diabetics) first-line beta-blockade has performed well in preventing myocardial infarction (a fact hidden by meta-analyses that do not take age into account). Conversely, in elderly hypertensives first-line beta-blockade (atenolol) has performed poorly in reducing cardiovascular risk (due to partial beta-2 blockade atenolol evokes metabolic disturbance and does not improve vascular compliance, or effectively lower central aortic pressure or reverse left ventricular hypertrophy). Thus beta-blockers like atenolol are ill-equipped for first-line therapy in elderly hypertension. Some beta-blockers, e.g. bisoprolol (up to 10 mg/day is highly beta-1 selective) and nebivolol (beta-2/3 intrinsic sympathomimetic activity), do improve vascular compliance and cause no metabolic disturbance. Beta-blockers as second-line to low-dose diuretics (which, by improving vascular compliance and increasing sympathetic nerve activity, create an optimal environment for beta-blockade) in elderly hypertension (including diabetics) have performed well in reducing cardiovascular events (this combination has the added bonus of reducing the risk of bone fracture by about 30%). Meta-analyses which include studies where it is unclear whether a diuretic or beta-blocker was a first-line therapy will dilute the benefit stemming from first-line diuretic/second-line beta-blockade. Hypertensives (of all ages) with ischaemia are well suited to beta-blockade.
... Также наиболее тяжело гипогликемия протекает у пациентов с СД 1-го типа 2 . Риск длительной гипогликемии предположительно был выше при применении неселективных β-блокаторов у пациентов, использующих инсулин или препараты сульфонилмочевины [31,32]. Однако не было выявлено существенной разницы в риске гипогликемии при использовании β-блокаторов в когорте 13 559 пожилых пациентов с СД по сравнению с пациентами без терапии β-блокаторами [31,32]. ...
... Риск длительной гипогликемии предположительно был выше при применении неселективных β-блокаторов у пациентов, использующих инсулин или препараты сульфонилмочевины [31,32]. Однако не было выявлено существенной разницы в риске гипогликемии при использовании β-блокаторов в когорте 13 559 пожилых пациентов с СД по сравнению с пациентами без терапии β-блокаторами [31,32]. При этом следует отметить, что была зарегистрирована тенденция к метаболической нейтральности в пользу кардиоселективных β-блокаторов по сравнению с неселективными представителями класса [31,32]. ...
... Однако не было выявлено существенной разницы в риске гипогликемии при использовании β-блокаторов в когорте 13 559 пожилых пациентов с СД по сравнению с пациентами без терапии β-блокаторами [31,32]. При этом следует отметить, что была зарегистрирована тенденция к метаболической нейтральности в пользу кардиоселективных β-блокаторов по сравнению с неселективными представителями класса [31,32]. ...
The presence of coexisting chronic non-infectious diseases is associated with reduced quality of life and increased risk of early disability and mortality. The coexistence of two or more diseases in a patient is defined by the term polymorbidity. Currently, there is an increase in polymorbid pathology not only among elderly patients, but also among young and middle-aged people, which entails significant health care costs and has a negative impact on the economy of the country as a whole. Therefore, the problem of polymorbidity and the management of such patients in real clinical practice is urgent and key in the field of public health. According to major foreign and domestic studies, the most common polymorbidity phenotype is the cardiometabolic phenotype. Taking into account the fact that in our country almost every second patient with arterial hypertension has metabolic disorders and, therefore, polymorbid pathology, approaches to the management of such patients should be personalized already from the beginning of drug therapy. In this regard, this review reviews some key pathophysiological mechanisms of the relationship between arterial hypertension and metabolic disturbances occurring in patients with the cardiometabolic phenotype of polymorbidity, presents features of antihypertensive therapy in such patients, in particular, describes in more detail the class of beta-blockers with pathogenetic validity of use in this case. Also, a review of the available clinical trial data concerning the effects of the highly selective beta-adrenoblocker bisoprolol in patients with arterial hypertension is presented, emphasizing its effect on metabolic status and its importance for comprehensive clinical management.
... • Inhibition of platelet aggregation [9,10] • Reduction of the mechanical stress imposed on coronary plaque, preventing its rupture • Resensitization of the β-adrenergic pathway and changes in myocardial gene expression (eg, an increase in sarcoplasmic reticulum calcium adenosine triphosphatase [ATPase], messenger ribonucleic acid [mRNA], and α-myosin heavy chain mRNA and a decrease in β-myosin heavy chain mRNA levels) • Inhibition of vascular smooth muscle cell proliferation [11] End-stage heart disease β-blockers also regulate cardiac apoptosis: β 1 stimulation increases apoptosis via a cyclic adenosine monophosphate (cAMP)-dependent mechanism, whereas stimulation of β 2receptors inhibits apoptosis via a Gi-coupled pathway. In selected patients with myocardial infarction (MI) or heart failure (HF), it is necessary to choose between a selective versus a nonselective β-blocker, because of the implication that β 1 -blockade would inhibit apoptosis, and β 2 -blockade may exacerbate this process [12,13]. Some β-blockers exhibit antioxidant properties; for example, bisoprolol reduces lipid peroxidation and attenuates the downregulation of peroxisome proliferation-activated receptor coactivator-1α, an important element in the mitochondrial reactive oxygen species detoxification system [14]; carvedilol maintains elevated levels of vitamin E [15]. ...
... β-blockers can exacerbate bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD) and mask symptoms of hypoglycemia in patients with type 1 insulin- . Nonselective β-blockers also induce weight increase (1-2 kg, 2.3-4.7 lb), because of the β 3 -receptor blockage decreasing lipolysis, fat oxidation, energy expenditure, and insulin sensitivity [12]. Other side effects include insomnia and sleeping disturbances (which are less common with nonlipophilic β-blockers), sexual dysfunction, and loss of libido. ...
... A moderately β 1 -selective agent such as atenolol is neutral and is relatively ineffective in lowering central aortic systolic pressure. Agents with β 2 / 3 ISA, such as nebivolol, pindolol, and celiprolol improve compliance, as does labelolol with additional α-blocking properties, and highly β 1 -selective bisoprolol [12]. ...
Cardiovascular diseases (CVDs) represent the most prevalent disorders in industrialized nations, and they are a rapidly growing problem in developing nations. In the last decades, several classes of pharmacological interventions (ie, antiplatelet agents, anticoagulant drugs, β-blockers, angiotensin-converting enzyme inhibitors, and statins) have proved highly effective in the prevention and treatment of CVD. Probably, the discovery of Β-blockers seems to be one of the most important developments in cardiovascular medicine. Several randomized clinical trials evaluated the effectiveness and safety of β-blockers in different clinical cardiac conditions. This review reports the principal pharmacological characteristics of β-blockers currently used in daily clinical practice. In addition, the principal studies in patients with myocardial infarction, heart failure, and stable coronary artery disease are analyzed. Finally, β-blocker use in patients with peripheral artery disease and chronic obstructive pulmonary disease is reported.
... Beta-blockers (BB) are widely used to treat patients with CVD. BB operate by reducing HR, systolic BP, the risk of plaque rupture, and microvascular damage [39]. Notably, Beta-1 blockade (common in BB) is accountable for a 35% reduction in ACM [39]. ...
... BB operate by reducing HR, systolic BP, the risk of plaque rupture, and microvascular damage [39]. Notably, Beta-1 blockade (common in BB) is accountable for a 35% reduction in ACM [39]. As BB impact heart rate, their influence on the prognostic value of HRR in patients requires further investigation, especially due to previous disagreements in the literature [9,20]. ...
Background:
The use of exercise testing has expanded in recent decades and there is a wealth of information examining the prognostic significance of exercise variables, such as peak oxygen consumption or ventilatory measures whilst exercising. However, a paucity of research has investigated the use of recovery-derived parameters after exercise cessation. Heart rate recovery (HRR) has been considered a measure of the function of the autonomic nervous system and its dysfunction is associated with cardiovascular risk.
Objectives:
We aim to provide an overview of the literature surrounding HRR and its prognostic significance in patients with cardiovascular disease undertaking an exercise test.
Data sources:
In December 2020, searches of PubMed, Scopus, and ScienceDirect were performed using key search terms and Boolean operators.
Study selection:
Articles were manually screened and selected as per the inclusion criteria.
Results:
Nineteen articles met inclusion criteria and were reviewed. Disagreement exists in methodologies used for measuring and assessing HRR. However, HRR provides prognostic mortality information for use in clinical practice.
Conclusions:
HRR is a simple, non-invasive measure which independently predicts mortality in patients with heart failure and coronary artery disease; HRR should be routinely incorporated into clinical exercise testing.
... celiprolol, pindolol, acebutolol, and oxprenolol) induce some activation of β 1 -receptors ("intrinsic sympathomimetic activity" [ISA]), which tends to limit reductions in myocardial performance and heart rate during β-blockade, and reduces the potential for peripheral vasoconstriction, if directed against peripheral β 2 adrenoreceptors [5]. The presence of ISA vs. no ISA does not appear to confer clinical benefit in patients with ischaemic heart disease (IHD) [6] or heart failure with reduced left ventricular ejection fraction (HFrEF) [7], however. ...
... 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.
... Individual drugs have differing selectivity for β 1 or β 2 receptors, some display limited activation of β receptors (intrinsic sympathomimetic activity), and some additional effects on α adrenoceptors, or promote release of nitric oxide (NO). 1 This review sets out to provide a pragmatic approach to understanding the therapeutic benefits and limitations of β-blockers in people with hypertension, ischemic heart disease (IHD; with or without prior myocardial infarction) or congestive heart failure (CHF) often associated in the same patient. ...
... 9 Selectivity and Metabolic Effects β-blockers may modestly increase triglycerides and decrease HDL-cholesterol, with little effect on LDL-cholesterol, although the presence of high β 1 -selectivity has been shown to ameliorate such effects. 1,10,11 These potential side effects should not present a barrier to the treatment of most patients, especially with a cardioselective drug. ...
blockers are a heterogeneous class of drugs, with varying selectivity/specificity for β1 vs β2 receptors, intrinsic sympathomimetic activity (ISA), and vasodilatory properties (through β2 stimulation, α receptor blockade or nitric oxide release). These drugs are indicated for the management of arterial hypertension, heart failure or ischemic heart disease (IHD; eg angina pectoris or prior myocardial infarction). Most of the benefit of β-blockade in these conditions arises from blockade of the β1 receptor, and, in practice, the addition of ISA appears to reduce the potential for improved clinical outcomes in people with heart failure or IHD. Aspects of the benefit/risk balance of β-blockers remain controversial, and recent meta-analyses have shed new light on this issue. We have reviewed the current place of cardioselective β-blockade in hypertension, IHD and heart failure, with special reference to the therapeutic profile of a highly selective β1-adrenoceptor blocker, bisoprolol.
... [2] The slower, the better? [3] Medical researchers also found that the beta-blockers without intrinsic sympathetic activity (ISA) significantly decreased the cardiovascular disease death (CVD death) and all-cause death than those with ISA, [4,5] which brought about relative prolongation of the patients' lifespan. Recently, a new drug called ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker, which selectively inhibits the If current to reduce the spontaneous pacemaker activity, but it presents no effect on ventricular repolarization and no effect on myocardial contractility. ...
... Considering that the beta-blockers' agents with ISA increase CVD mortality, thus they are not used in the management of CAD, heart failure, and tachyarrhythmia. [5,6] It is inescapably clear that the endogenous long-lasting sympathetic hyperactivity play an key role on increasing CVD mortality and all-cause mortality. ...
Background:
It has long been a controversial hotspot whether resting heart rate (RHR) is a risk factor or a marker for death. Ivabradine, a specific inhibitor of the If current in the sinoatrial node, is a pure RHR lowering agent. The study was aimed to investigate whether ivabradine would reduce more RHR, cardiovascular disease (CVD) mortality, and all-cause mortality than those placebo or beta-blockers.
Methods:
The authors performed a meta-analysis of 8 randomized controlled clinical studies (with 40,357 participants), and 3 studies of those which were ivabradine versus placebo (36,069 participants) and other 5 studies ivabradine versus beta-blockers (4288 participants) were available. The authors compared the association of the RHR reduction with death from CVD causes (2674 in 40,285 participants) and the rate of all-cause death (3143 deaths in 38,037 participants), and assessed improvement in death rates with the use of ivabradine.
Results:
The change of RHR from baseline to endpoint was 8 to 16 beats/min (bpm) in ivabradine group, 1 to 8 bpm in placebo group, and 4 to 24 bpm in beta-blockers group. In ivabradine versus placebo, the reduced risks of CVD mortality and all-cause morbidity were not significantly (risk ratio [RR] 1.02; 95% confidence interval [CI] 0.91-1.14, P = .737; RR: 1.00, 95% CI: 0.92-1.09, P = .992, respectively). CVD and all-cause morbidity were similar for ivabradine versus beta-blockers (RR: 1.04; 95% CI: 0.80-1.37, P = .752; RR: 1.17, 95% CI: 0.53-2.60, P = .697, respectively).
Conclusions:
Ivabradine had a neutral effect on mortality, suggesting that a pure RHR lowering agent did not reduce CVD mortality, all-cause mortality and improve the lifespan.
... The main rationale for perioperative b-blocker use is to decrease myocardial oxygen consumption by reducing heart rate, resulting in a lengthening of the diastolic filling period, and decreased myocardial contractility. 72 Additional cardioprotective factors are redistribution of coronary blood flow to the subendocardium, plaque stabilization, and an increase in the threshold for ventricular fibrillation. 72 Randomized studies have shown that b-blockers and other drugs that lower the heart rate can reduce perioperative myocardial ischaemia as assessed by continuous ST-segment monitoring. ...
... 72 Additional cardioprotective factors are redistribution of coronary blood flow to the subendocardium, plaque stabilization, and an increase in the threshold for ventricular fibrillation. 72 Randomized studies have shown that b-blockers and other drugs that lower the heart rate can reduce perioperative myocardial ischaemia as assessed by continuous ST-segment monitoring. 73 However, whether this translates into a clinical benefit can be established only through trials analysing the incidence of cardiovascular events. ...
The disclosure forms of all the authors and reviewers are available on the ESC website www.escardio.org/guidelines.
... These guidelines do not recommend BBs as initial therapy for patients unless there are compelling indications. For example, they may be considered for young/middle aged patients, since many of them have an increased sympathetic nervous system activity [33][34][35] . For patients receiving first-line BB treatment who require combination therapy, the use of a CCB rather than a thiazide-like diuretic for the second drug is recommended. ...
... While tobacco smokers may receive any combination of antihypertensive classes, highly selective BBs such as bisoprolol or nebivolol are recommended, whereas the less selective BBs should be avoided. This is because smoking increases sympathetic-induced vasoconstriction and the BP lowering effect of less selective BBs will be diminished by unopposed vasoconstriction due to their inhibition of beta2-receptor-mediated vasodilation with concomitant stimulation of alpha-receptors [33][34][35] . ...
Abstract Hypertension incurs a significant healthcare burden in Asia-Pacific countries, which have suboptimal rates of blood pressure (BP) treatment and control. A consensus meeting of hypertension experts from the Asia-Pacific region convened in Hanoi, Vietnam, in April 2013. The principal objectives were to discuss the growing problem of hypertension in the Asia-Pacific region, and to develop consensus recommendations to promote standards of care across the region. A particular focus was recommendations for combination therapy, since it is known that most patients with hypertension will require two or more antihypertensive drugs to achieve BP control, and also that combinations of drugs with complementary mechanisms of action achieve BP targets more effectively than monotherapy. The expert panel reviewed guidelines for hypertension management from the USA and Europe, as well as individual Asia-Pacific countries, and devised a treatment matrix/guide, in which they propose the preferred combination therapy regimens for patients with hypertension, both with and without compelling indications. This report summarises key recommendations from the group, including recommended antihypertensive combinations for specific patient populations. These strategies generally entail initiating therapy with free drug combinations, starting with the lowest available dosage, followed by treatment with single-pill combinations once the BP target has been achieved. A single reference for the whole Asia-Pacific region may contribute to increased consistency of treatment and greater proportions of patients achieving BP control, and hence reducing hypertension-related morbidity and mortality.
... Меньшую эффективность атенолола по сравнению с другими антигипертензивными препаратами некоторые авторы объясняют его неблагоприятным влиянием на липидный состав крови и чувствительность к инсулину [103]. Кроме того, ранее показано, что у курящих пациентов с АГ молодого и среднего возраста, составлявших 1 / 3 популяции, риск развития ССО увеличивается в 2 раза, а неселективные или частично селективные β-адреноблокаторы практически не влияют на прогноз [104]. Вместе с тем известно, что нарушения липидного и углеводного обменов связаны в большей степени с блокадой β 2 -рецепторов, а высокоселективные β 1 -адреноблокаторы (бисопролол) и β-адреноблокаторы с внутренней симпатомиметической активностью или α-блокирующими свойствами (небиволол, карведилол) не оказывают отрицательного влияния на метаболический профиль [104][105][106]. ...
... Кроме того, ранее показано, что у курящих пациентов с АГ молодого и среднего возраста, составлявших 1 / 3 популяции, риск развития ССО увеличивается в 2 раза, а неселективные или частично селективные β-адреноблокаторы практически не влияют на прогноз [104]. Вместе с тем известно, что нарушения липидного и углеводного обменов связаны в большей степени с блокадой β 2 -рецепторов, а высокоселективные β 1 -адреноблокаторы (бисопролол) и β-адреноблокаторы с внутренней симпатомиметической активностью или α-блокирующими свойствами (небиволол, карведилол) не оказывают отрицательного влияния на метаболический профиль [104][105][106]. ...
... Moreover, in a number of studies [14,[18][19][20][21][22], atenolol-based therapy was significantly less effective for lowering aortic systolic and pulse pressure, which may be attributed to a different mechanism of atenolol, thus explaining the different clinical outcomes. Since b-blocking drugs might have heterogeneous effects on the arterial system and BRS depending on their pharmacologic properties, further comparisons of the effects of BBs on the arterial system and BRS may be helpful [23]. Bisoprolol, with its high b1-selectivity, long duration of action, and favorable pharmacokinetic properties, was shown to be an effective and safe antihypertensive agent [24,25]. ...
... Three factors can explain the reasons for the more important decrease in CAP with bisoprolol: first, because of its high selectivity towards b1 adrenergic receptors vs. b2 receptors (at doses up to 10 mg, 0-5% of b2 receptors are blocked), bisoprolol blocks a lower number of b2 receptors than does atenolol (at a daily dose of 100 mg, approximately 25% of b2 receptors are blocked) [23]. It is reported that b2 stimulation causes vasodilatation, benefiting arterial elasticity, and lowers CAP [35]; b2 blockade would antagonize this potentially beneficial process. ...
β-blockers (BBs) with different pharmacological properties may have heterogeneous effects on sympathetic nervous activity (SNA) and central aortic pressure (CAP), which are independent cardiovascular factors for hypertension. Hence, we analyzed the effects of bisoprolol and atenolol on SNA and CAP in hypertensive patients.
This was a prospective, randomized, controlled study in 109 never-treated hypertensive subjects randomized to bisoprolol (5 mg) or atenolol (50 mg) for 4-8 weeks. SNA, baroreflex sensitivity (BRS) and heart rate (HR) variability (HRV) were measured using power spectral analysis using a Finometer. CAP and related parameters were determined using the SphygmoCor device (pulse wave analysis).
Both drugs were similarly effective in reducing brachial BP. However, central systolic BP (-14±10 mm Hg vs -6±9 mm Hg; P<0.001) and aortic pulse pressure (-3±10 mm Hg vs +3±8 mm Hg; P<0.001) decreased more significantly with bisoprolol than with atenolol. The augmentation index at a HR of 75 bpm (AIxatHR75) was significantly decreased (29%±11% to 25%±12%; P = 0.026) in the bisoprolol group only. Furthermore, the change in BRS in the bisoprolol group (3.99±4.19 ms/mmHg) was higher than in the atenolol group (2.66±3.78 ms/mmHg), although not statistically significant (P>0.05). BRS was stable when RHR was controlled (RHR≤65 bpm), and the two treatments had similar effects on the low frequency/high frequency (HF) ratio and on HF.
BBs seem to have different effects on arterial distensibility and compliance in hypertensive subjects. Compared with atenolol, bisoprolol may have a better effect on CAP.
ClinicalTrials.gov NCT01762436.
... Beta blockers, such as Bisoprolol, lower blood pressure and heart rate, and are widely used for the treatment of hypertension, tachycardia, cardiac angina, and heart failure in adults [5]. In particular, Bisoprolol is widely used for the prevention of cardiovascular events following a heart attack in patients with risk factors [4,6], arrhythmias [7], and as a second-line agent for hypertension [8]. ...
In complex suicides, more than one suicide method is applied at the same time or one after the other. The most common complex suicide includes the ingestion of drugs combined with drowning. A case of acute intoxication by Bisoprolol and drowning is reported. The dead body of a 40-year-old woman was discovered on a river side, soon after her husband found a suicide note at home. In the woman’s vehicle four empty boxes of Bisoprolol, a widely used beta blocker, were also found. Main autopsy findings were consistent with drowning and represented by plume of froth at the mouth and nostrils with frothy fluid also in the airways, water into the stomach, and a remarkable pulmonary edema as a result of fluid aspiration. Toxicological analyses were performed on peripheral blood, urine and gastric content samples using liquid and gas chromatography, coupled with mass spectrometry. Toxicological results were negative for ethanol and other common drugs of abuse. High levels of bisoprolol were found in blood (7.54 mg/L), far exceeding the therapeutic range, in the urine (1.14 mg/L), and gastric content (13.12 mg/L). Bisoprolol intoxication was assessed as a relevant contributing condition to the immediate cause of death represented by drowning. Although Bisoprolol would certainly have a heart-depressing effect, it is not possible to determine if the victim fell unconscious or if she simply collapsed into the water with a secondary drowning.
... This study proposed a non-contact piezoelectric sensing-based HF detection scheme, which can provide the robust performance for HF (LVEF ≤ 49%) detection without the quality assessment of BCG signals. Considering that the HF is the end-stage of all cardiovascular diseases, many HF patients usually have mitral and tricuspid regurgitation and suffer from low vascular compliance (Cruickshank, 2007). These kinds of heart diseases may cause the irregularity in the beat-to-beat BCG morphology, and bring challenge in the HF detection (Aydemir et al., 2019;Chang et al., 2020). ...
Purpose: Under the influence of COVID-19 and the in-hospital cost, the in-home detection of cardiovascular disease with smart sensing devices is becoming more popular recently. In the presence of the qualified signals, ballistocardiography (BCG) can not only reflect the cardiac mechanical movements, but also detect the HF in a non-contact manner. However, for the potential HF patients, the additional quality assessment with ECG-aided requires more procedures and brings the inconvenience to their in-home HF diagnosis. To enable the HF detection in many real applications, we proposed a machine learning-aided scheme for the HF detection in this paper, where the BCG signals recorded from the force sensor were employed without the heartbeat location, and the respiratory effort signals separated from force sensors provided more HF features due to the connection between the heart and the lung systems. Finally, the effectiveness of the proposed HF detection scheme was verified in comparative experiments.
Methods: First, a piezoelectric sensor was used to record a signal sequences of the two-dimensional vital sign, which includes the BCG and the respiratory effort. Then, the linear and the non-linear features w.r.t. BCG and respiratory effort signals were extracted to serve the HF detection. Finally, the improved HF detection performance was verified through the LOO and the LOSO cross-validation settings with different machine learning classifiers.
Results: The proposed machine learning-aided scheme achieved the robust performance in the HF detection by using 4 different classifiers, and yielded an accuracy of 94.97% and 87.00% in the LOO and the LOSO experiments, respectively. In addition, experimental results demonstrated that the designed respiratory and cardiopulmonary features are beneficial to the HF detection (LVEF ≤ 49 % ).
Conclusion: This study proposed a machine learning-aided HF diagnostic scheme. Experimental results demonstrated that the proposed scheme can fully exploit the relationship between the heart and the lung systems to potentially improve the in-home HF detection performance by using both the BCG, the respiratory and the cardiopulmonary-related features.
... Beta-blockers are the mainstay treatment in the management of CHF with reduced ejection fraction. Different drugs have varying selectiveness for beta 1 or 2 receptors: some only partially activate the receptors (inherent sympathomimetic action), some have supplementary belongings on adrenoceptors, or they may stimulate the production of nitric oxide [14]. The majority of commonly used beta-blockers (metoprolol, carvedilol, propranolol, nebivolol, and bisoprolol) are contrary agonists at the beta 1 adrenoceptor, which means that exposure to the drug reduces a predominating basal level and constitutionally decreased signal transduction from the receptor even in the absence of an agonist for the receptor [15]. ...
Congestive heart failure (CHF) is a complex, heterogeneous medically ill condition that can occur due to diverse primary (cardiomyopathies, coronary artery diseases, and hypertension) and secondary causes (high salt intake and noncompliance toward treatment) and leads to significant morbidity and mortality. The approach toward managing the patient of CHF in the pediatric age group is more complex than in the adult population. Currently, in the adult group of the population of CHF, there are well-established guidelines for managing these patients, but in the case of children, there are no well-established guidelines; therefore, this systematic review gives more ideas for managing the pediatric population undergoing CHF. Treatment of the underlying cause, rectification of any advancing event, and management of pulmonary or systemic obstruction are the principles for management. The most widely used drugs are diuretics and angiotensin-converting enzyme (ACE) inhibitors, whereas beta-blockers are less commonly used in children than in adults. ACE inhibitors such as captopril, enalapril, and cilazapril are widely used in the pediatric age group. ACE inhibitors act on the renin-angiotensin-aldosterone system (RAAS) similar to those in the adult population. In children with heart failure (HF), ACE inhibitors reduce the pressure in the aorta, resistance in the systemic blood vessels, and upper left and right chamber pressures but do not appreciably influence pulmonary vascular resistance. We use a patient's initial perfusion and volume status assessment to decide further action for the supervision of acute HF. This paradigm was adopted from adult studies that showed higher rates of morbidity and mortality in patients with HF whose hemodynamic or volume status assessment results were stable with a pulmonary capillary wedge pressure >18 mmHg and a combined index (CI) of 2.2 L/minute/m2. ACE inhibitors, beta-blockers, and spironolactone are the most widely prescribed drugs for the chronic condition of CHF. This study shows the current status of medical therapy for critical as well as persistent pediatric HF.
... Chronic stimulation of β-adrenergic receptors (βARs) induces adverse cardiac remodeling via Gαs protein-dependent pathways such as protein kinase A (PKA) signaling [1][2][3][4][5], which is a therapeutic basis for βAR antagonists (β-blockers) in heart failure (HF) [6][7][8]. However, β-blockers can have detrimental effects [9,10], and the actions of individual β-blockers are divergent [11]. Thus, a better understanding of signaling events downstream of βAR is needed for developing novel HF therapeutics. ...
The β 1 -adrenergic receptor (β 1 AR) is found primarily in hearts (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β 1 AR signaling elicits cardioprotection through CM survival. We showed that microRNA-150 (miR-150) is upregulated by β-arrestin-mediated β 1 AR signaling and that CM miR-150 inhibits maladaptive remodeling post-myocardial infarction. Here, we investigate whether miR-150 rescues cardiac dysfunction in mice bearing CM-specific abrogation of β-arrestin-mediated β 1 AR signaling. Using CM-specific transgenic (TG) mice expressing a mutant β 1 AR (G protein-coupled receptor kinase [GRK] – β 1 AR that exhibits impairment in β-arrestin-mediated β 1 AR signaling), we first generate a novel double TG mouse line overexpressing miR-150. We demonstrate that miR-150 is sufficient to improve cardiac dysfunction in CM-specific GRK – β 1 AR TG mice following chronic catecholamine stimulation. Our genome-wide circular RNA, long noncoding RNA (lncRNA), and mRNA profiling analyses unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for beneficial actions of β 1 AR/β-arrestin signaling or miR-150. We further show that lncRNA Gm41664 and GDAP1L1 are direct novel upstream and downstream regulators of miR-150. Lastly, CM protective actions of miR-150 are attributed to repressing pro-apoptotic GDAP1L1 and are mitigated by pro-apoptotic Gm41664. Our findings support the idea that miR-150 contributes significantly to β 1 AR/β-arrestin-mediated cardioprotection by regulating unique ncRNA and gene signatures in CMs.
... A total of 78 eligible patients were invited to participate in the study but 19 subjects were excluded during β-blockers, was significantly less effective for lowering CASP and central pulse pressure (C-PP) than other therapies [4,12]. However, there are fewer studies on the effects on CASP with bisoprolol, which is a highly β 1 -selective β-blocker that may have advantages over less selective β-blockers in the treatment of hypertension, such as less adverse metabolic effects [13]. ...
We conducted a prospective open-label cohort study with the aim of examining the effects of the highly β1-selective agent bisoprolol on central aortic systolic pressure (CASP) after the first dose and after 6 weeks’ treatment and whether the CASP response could be predicted from the early response. Chinese patients with primary hypertension (BP ≥ 140/90 mmHg) on no therapy or background amlodipine were treated with bisoprolol 2.5 mg daily for 6 weeks. Brachial systolic BP (Br-SBP), resting heart rate (HR) and CASP were determined at baseline, 24h after the first dose, and pre-dose after treatment for 6 weeks using the BPro® device. In 42 patients (age 54 ± 9 years) the mean reductions in CASP and Br-SBP after 6 weeks of treatment were not significantly different from each other at -14.5 ± 12.7 and -15.4 ± 12.9 mmHg (both p<0.01), respectively. Changes in CASP and Br-SBP were highly correlated after the first dose (r = 0.964, p<0.01) and after 6 weeks (r = 0.963, p<0.01) and the reductions in CASP after 6 weeks were also associated with the reduction in CASP after the first dose (r = 0.577, p<0.01). Bisoprolol was shown to effectively reduce CASP and this effect was directly proportional to the reduction in Br-SBP and of a similar magnitude. More favourable CASP responses to long term therapy may be predicted by greater reductions in CASP after the first dose.
... 25,108,109 Reduced CO secondary to reduced HR and SV is primarily responsible for beta blocker-related hypotension, especially when using beta blockers that do not have intrinsic sympathomimetic activity. 111 Although there may be a decrease in coronary perfusion pressure because of hypotension, beta blockers may augment coronary blood flow by increasing diastolic perfusion time via HR slowing 112 or by coronary vasodilation. 113 The level I recommendation for initiating oral beta blockers within the first 24 h in patients with non-ST-elevation acute coronary syndromes in the absence of heart failure, low-output state, risk of cardiogenic shock, or other contraindications highlights beta blockers' beneficial effect on the myocardial metabolic demandesupply balance. ...
Arterial blood pressure is the driving force for organ perfusion. Although hypotension is common in acute care, there is a lack of accepted criteria for its definition. Most practitioners regard hypotension as undesirable even in situations that pose no immediate threat to life, but hypotension does not always lead to unfavourable outcomes based on experience and evidence. Thus efforts are needed to better understand the causes, consequences, and treatments of hypotension. This narrative review focuses on the heterogeneous underlying pathophysiological bases of hypotension and their impact on organ perfusion and patient outcomes. We propose the iso-pressure curve with hypotension and hypertension zones as a way to visualize changes in blood pressure. We also propose a haemodynamic pyramid and a pressure–output–resistance triangle to facilitate understanding of why hypotension can have different pathophysiological mechanisms and end-organ effects. We emphasise that hypotension does not always lead to organ hypoperfusion; to the contrary, hypotension may preserve or even increase organ perfusion depending on the relative changes in perfusion pressure and regional vascular resistance and the status of blood pressure autoregulation. Evidence from RCTs does not support the notion that a higher arterial blood pressure target always leads to improved outcomes. Management of blood pressure is not about maintaining a prespecified value, but rather involves ensuring organ perfusion without undue stress on the cardiovascular system.
... However, treatment with beta blockers may be a viable option in lower risk patients, in whom the benefit-harm tradeoff is in favor of beta blockers. This is in accordance with earlier findings that beta blockers should be considered as first-line treatment for younger hypertensive patients [21,23]. More thorough evaluation of these results is required in future research. ...
Aim: One of the aims of the Observation Health Data Sciences and Informatics (OHDSI) initiative is population-level treatment effect estimation in large observational databases. Since treatment effects are well-known to vary across groups of patients with different baseline risk, we aimed to extend the OHDSI methods library with a framework for risk-based assessment of treatment effect heterogeneity. Materials and Methods: The proposed framework consists of five steps: 1) definition of the problem, i.e. the population, the treatment, the comparator and the outcome(s) of interest; 2) identification of relevant databases; 3) development of a prediction model for the outcome(s) of interest; 4) estimation of propensity scores within strata of predicted risk and estimation of relative and absolute treatment effect within strata of predicted risk; 5) evaluation and presentation of results. Results: We demonstrate our framework by evaluating heterogeneity of the effect of angiotensin-converting enzyme (ACE) inhibitors versus beta blockers on a set of 9 outcomes of interest across three observational databases. With increasing risk of acute myocardial infarction we observed increasing absolute benefits, i.e. from -0.03% to 0.54% in the lowest to highest risk groups. Cough-related absolute harms decreased from 4.1% to 2.6%. Conclusions: The proposed framework may be useful for the evaluation of heterogeneity of treatment effect on observational data that are mapped to the OMOP Common Data Model. The proof of concept study demonstrates its feasibility in large observational data. Further insights may arise by application to safety and effectiveness questions across the global data network.
... contains supplementary material, which is available to authorized users. insulin sensitivity, changes in triglyceride and lipoprotein levels) are associated with β2 and β3 receptor blockade [9,10]. Accordingly, using β1-selective agents, deterioration of metabolic parameters can be avoided or substantially reduced [8]. ...
PurposeGiven that it has been reported that type 2 diabetes mellitus may affect the pharmacokinetics of a large number of drugs and that there are still no published population pharmacokinetic (PopPK) analyses in routinely treated patients with hypertension and type 2 diabetes mellitus as comorbid condition, the aim of this study was to determine PK variability of bisoprolol in 70 Serbian patients using the PopPK approach.Methods
PopPK analysis was conducted using a nonlinear mixed effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In our patients, a total daily dose of bisoprolol ranged from 1.25 to 10 mg. The drug was administrated orally as a single daily dose or in two divided doses per day.ResultsA wide range of the drug concentrations were noted (1–103 ng/mL) in the population consisted of the adult patients with type 2 diabetes mellitus. From a total of 21 separately assessed covariates, our results indicated that only creatinine clearance could have a potential impact on the variability of the clearance of bisoprolol.Conclusion
Routine assessment of renal function should be carried out before the initiation of treatment with bisoprolol in order to individualize the dose and to prevent possible accumulation and adverse drug reactions.
... Bu metabolik etkileri esas olarak β2 ve β3 reseptör blokajı ile ilişkilidir. [39,40] Non-selektif ajanlar metabolik parametreleri bozabilirken bu ihtimal β1 selektif ajanlarda (bisoprolol, metoprolol) daha azdır ancak vazodilatör beta blokerlerde, β2 sempatomimetik aktiviteye sahip (nebivolol) ve alfa blokaj özelliği olan (carvedilol), görülmez. [41][42][43] Kalp yetersizliği olan diyabetik hastalarda beta blokerler tercihan vazodilatör özellikli carvedilol ve nebivolol diyabetik olmayanlarda olduğu gibi sınıf I endikasyon ile önerilmektedir. ...
... Although there are some authors who recommend caution in perioperative management of beta-blockers, there is a general recommendation to regulate perioperative hypertension by using beta blockers whenever is possible, since these drugs can safely be combined with general anesthetics [9,37,40]. Th e main reason for perioperative beta blocker use is decrease of myocardial oxygen consumption by reducing heart rate, resulting in a lengthening of the diastolic fi lling period and decreased myocardial contractility [41]. Perioperative beta blocker therapy can provide a 60-65% reduction in the likelihood of non-fatal myocardial infarction and cardiac death [42]. ...
Introduction: Perioperative healthcare represents the care of the patient's health, before, during and after surgical intervention. There is a lot of clinical studies that confi rm high incidence of cardiovascular and respiratory events during perioperative period, especially in patients who already suff er from chronic disorders of these organs and organ systems, which can be successfully prevented or minimized by adequate drug management. Methods: This paper is based on information from other reviews, clinical studies and textbooks, along with clinical experience, professional and theoretical considerations about cardiovascular and respiratory disorders' drug management in perioperative healthcare. Topics: This manuscript contains clinically relevant information about eff ects and adverse eff ects of intravenous and inhalational general anesthetics on the cardiovas-cular and respiratory system, as well as general and special recommendations for pe-rioperative drug management in patients with hypertension, angina pectoris, cardiac arrhythmias, bronchial asthma, and chronic obstructive pulmonary disease (COPD). Conclusion: Postoperative recovery process may be seriously slowed down by peri-operative cardiovascular and respiratory events, especially those which can directly endanger the patient's life before, during and after general anesthesia and surgery. The take-home message of this article is that most of the potential perioperative car-diovascular and respiratory complications can be successfully prevented by rational and individually tailored drug management in perioperative period.
... b-Adrenoceptor (AR) antagonists (b-blockers) block catecholamines from binding to b-AR, which reduces heart rate (HR) and the force of contraction, thereby reducing myocardial oxygen demand (1,2). Randomized, placebocontrolled clinical trials demonstrate mortality reductions with b-blockers of 34 to 35% in patients with heart failure and of 36 to 39% in patients with myocardial infarction (3)(4)(5)(6)(7). ...
β-Blockers reduce mortality and improve symptoms in people with heart disease; however, current clinically available β-blockers have poor selectivity for the cardiac β1-adrenoceptor (AR) over the lung β2-AR. Unwanted β2-blockade risks causing life-threatening bronchospasm and reduced efficacy of β2-agonist emergency rescue therapy. Thus, current life-prolonging β-blockers are contraindicated in patients with both heart disease and asthma. Here, we describe NDD-713 and -825, novel highly β1-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed in Chinese hamster ovary cells demonstrate that NDD-713 and -825 have nanomolar β1-AR affinity >500-fold β1-AR vs β2-AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced β1-mediated reduction of heart rate while showing no effect on β2-mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective β-blocker therapy for the large number of patients with heart and respiratory or peripheral vascular comorbidities.-Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., Thompson, K. S. J., Kellam, B., Hill, S. J., Fischer, P. M. Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.
... Although β-blockers have been widely used in the treatment of endoscopic sinus surgery (30), hypertension, coronary artery disease, dilated cardiomyopathy and heart failure (27,31), the clinical efficacy among different β-blockers does not appear to be equivalent (32). In the present study, different doses of a highly selective β 1 -AR-blocking antagonist, bisoprolol, not metoprolol (which induces fibrosis and cardiac dysfunction) (33) was used in order to improve cardiac function in the AB model. ...
Bisoprolol is a drug that acts via the mechanism of specifically and selectively inhibiting the β1-adrenoreceptor in cardiac myocytes, and provides a pure reduction of heart rate without changing other cardiac parameters. It has long been clinically used to treat cerebrovascular and cardiovascular illnesses. However, there is little information available on whether the role of bisoprolol in the attenuation of ventricular remodeling is dependent upon the achievement of a target dose, and whether it must be used as a preferred option. The aim of the present study was to clarify the underlying benefits of bisoprolol in the attenuation of pressure overload-induced cardiac hypertrophy and fibrosis at different doses. C57BL/6J male mice, aged 6-8 weeks, were treated with saline or one of three different doses of bisoprolol (Biso: 2.5, 5 or 10 mg/kg/day) for 8 weeks from day 1 after aortic banding (AB). A number of mice underwent sham surgery and were treated with saline or bisoprolol. The mice were randomly assigned into the sham (n=24) and AB (n=62) groups. The results revealed that bisoprolol had a protective role against the cardiac hypertrophy, fibrosis and dysfunction caused by AB. This was determined on the basis of heart/body and lung/body weight ratios and heart weight/tibia length ratios, as well as echocardiographic and hemodynamic parameters, histological analysis, and the gene expression levels of hypertrophic and fibrotic markers. The present study revealed that administration of bisoprolol for a long time period may enhance its role in the prevention of cardiac hypertrophy and fibrosis induced by AB, whereas no statistically significant difference was observed between the middle- and high-doses. These observations indicated that the function of bisoprolol in protecting against cardiac hypertrophy, fibrosis and dysfunction is time-dependent. Furthermore, it is proposed that a middle dose of bisoprolol may be a better option for patients with cardiovascular illnesses, particularly those undertaking coronary artery bypass graft and cardiac pacemaker surgeries. These promising results require further clinical investigation.
... This prolongs diastolic filling time and reduces contractility. 91 Recent studies, however, have rekindled the old controversy over the use of beta-blockers in noncardiac surgery. 92 Preoperative suspension of beta-blockers in HF patients is not justified, and if they have not previously been given but are indicated, they should be started. ...
In 1977, Goldman advised against surgery in patients with heart failure (HF). Nowadays, however, these patients are regularly scheduled for surgery in our hospitals, and the trend is likely to increase in the future. This is because although incidence of cardiac death is falling, the prevalence of ischaemic heart disease, atrial fibrillation (AF), and cardiovascular risk factors such as diabetes mellitus or HTN is increasing, and will no doubt create a greater demand for surgery in these patients in the near future.
It is widely accepted that between 1% and 6% of patients undergoing major surgery have heart failure. This percentage is expected to increase, because the average age of surgical patients requiring major surgery is rising, and because the prevalence of HF with preserved EF increases with age.
Ischaemic heart disease is traditionally associated with increased morbidity and mortality in patients undergoing noncardiac surgery. However, we now know that HF is the primary intraoperative risk factor in cardiovascular disease patients undergoing noncardiac surgery.
Despite its undoubted importance, HF is frequently underestimated, possibly due to epidemiological reasons. Let us not forget that HF is the third cause of death (15%) from cardiovascular disease after ischaemic heart disease and cerebrovascular disease, which together are responsible for 60% of deaths. The real importance of HF, however, is underestimated, because many patients that die from ischaemic heart disease or cerebrovascular disease also have HF, which to a certain extent contributes to their death.
Clinical Practice Guideline (CPG). Recommendations on strategy for reducing risk of heart failure patients requiring noncardiac surgery. Available from: https://www.researchgate.net/publication/280006425_Clinical_Practice_Guideline_CPG_Recommendations_on_strategy_for_reducing_risk_of_heart_failure_patients_requiring_noncardiac_surgery
... Potential benefits of b-blocker therapy include decreased oxygen demand due to reductions in heart rate, blood pressure, and contractility, and an increase in diastolic filling time, with the consequent relief of ischemic chest pain 40,69 , as well as a reduction in risk of cardiovascular events compared with all other antihypertensive agents 70 , and a reduction in risk of death 71 . Such benefits are conferred through b-1 blockade and are not found in b-blockers with intrinsic sympathomimetic activity, which should be avoided 40,72 . Of particular relevance to understanding why b-blockers are underused is the profile of those patients who are less likely to initiate therapy with b-blockers. ...
Background:
Cardiovascular diseases, to which coronary artery disease (CAD) is a significant contributor, are a leading cause of long-term morbidity and mortality worldwide. In the years ahead, it is estimated that approximately half of the world's cardiovascular burden will occur in the Asian region. Currently there is a large gap in secondary prevention, with unrealized health gains resulting from underuse of evidence-based medications, including beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aspirin and other antiplatelet agents, and lipid-lowering drugs. Despite the almost universal recommendation for these drugs in unstable CAD, their under-prescription is well documented for patients with acute heart failure, non-obstructive CAD, and for secondary prevention of CAD.
Objective:
This article reviews the burden of CAD in Asian countries together with guidelines supporting evidence-based medication use from a secondary prevention perspective.
Methods:
The MEDLINE database was searched from 2000 to 2013, inclusive, for country-specific data related to CAD and supplemented with unpublished registry data.
Results:
In the post-discharge setting following hospital admission for acute coronary syndromes, medication prescription rates were low. Beta-blocker prescription rates ranged from 49% in China to 99% in Singapore, ACE-inhibitor/ARB prescription rates ranged from 28% in China to 96% in Singapore, and lipid-lowering therapy rates ranged from 47% in China to 97% in Singapore. Aspirin/antiplatelet drug prescription rates ranged from 86% in Indonesia to 99.5% in Singapore. Recommendations are provided to improve patient outcomes and reduce the disease burden in Asia.
Conclusions:
Despite recommendations issued in international and national guidelines, use of CAD medications in Asia remains suboptimal. In the absence of clear contraindications, all patients with unstable CAD should receive these agents as secondary prevention. This averts the need to target drug use according to risk, with high-risk features paradoxically associated with under-prescribing of such drugs.
... Un altro punto cruciale riguarda l'utilizzo di strategie farmacologiche per la cardioprotezione perioperatoria, in particolare l'uso dei beta-bloccanti, soprattutto in soggetti anziani. Il razionale per l'uso preoperatorio e peri-operatorio dei betabloccanti si basa sulla riduzione del consumo miocardico di ossigeno attraverso una diminuzione della frequenza cardiaca, un prolungamento della fase di riempimento diastolico ed una riduzione della contrattilità miocardica [17]. La titolazione della posologia del betabloccante, effettuata gradualmente sulla base della riduzione della frequenza cardiaca, evitando l'ipotensione, è associata ad un miglior outcome cardiovascolare [18]. ...
Non cardiac surgery is becoming increasingly common in elderly patients; they are usually affected by overt cardiac disease or show multiple risk factors, responsible for a higher incidence of perioperative fatal or nonfatal cardiac events. Of interest, acute myocardial infarction occurring in the perioperative period shows a high mortality rate in people over 65 years old. The cardiovascular risk stratification and perioperative management of subjects undergoing noncardiac surgery have been recently updated in the 2014 European Society of Cardiology Guidelines. However, several critical points still lack of strong evidence and are based on expert opinions only. For example, the use of drugs, such as beta-blockers, before, during and after the surgery, presents many uncertainties regarding the selection of patients more likely to benefit, dosage and duration of therapy, and effects on outcome. Data on elderly patients undergoing non cardiac surgery are scarce. Accordingly, a prospective registry enrolling a large number of aged subjects undergoing non cardiac surgery (particularly at high or intermediate risk) should be able to give us adequate insights on the management strategies currently used, on the incidence of death or cardiovascular events in the postoperative period and on the areas of potential improvement in care. Furthermore, the effects on outcome of structured programs of Guidelines implementation in the clinical practice of cardiologists, anesthesiologists and other health personnel involved in perioperative care, could be positive and should be evaluated.
... La presión Cuadro I. Estratifi cación del riesgo cardiovascular en cuatro categorías. Sin FR Riesgo Riesgo Bajo riesgo Riesgo adicional Alto riesgo promedio [1] promedio [2] adicional [3] moderado [4] adicional [5] 1-2 FR Bajo riesgo Bajo riesgo Riesgo adicional Riesgo adicional Muy alto riesgo adicional [6] adicional [7] moderado [8] moderado [9] adicional [10] ≥ 3 FR, SM, Riesgo adicional Alto riesgo Alto riesgo Alto riesgo Muy alto riesgo daño subclínico a moderado [11] adicional [12] adicional [13] adicional [14] adicional [15] ...
Hypertension is poorly controlled in most patients. The control rate, defined as a systolic blood pressure (SBP) < 140 mmHg and diastolic blood pressure (DBP) < 90 mmHg, is less than 20% in Mexico. This study involving 31 research centers, carried out under real conditions was designed to establish that 6.25 mg of hydrochlorothiazide (HCTZ) given once daily in fixed combination with 2.5 mg or 5 mg of bisoprolol fumarate can contribute to achieve the control targets in patients with grade I, II or III systemic hypertension who failed to a previous antihypertensive regimen, and that these combinations are safer than the drugs alone. The results showed significant mean decreases in systolic and diastolic blood pressure of 33.3 mmHg and 18.4 mmHg respectively. The response rate was 85.7% at 32 weeks of treatment. There was a decrease in mean heart rate of 10.8 beats/min, final average heart rate was 67.05 beats per minute. The results of this study show that the combination of bisoprolol in doses of 2.5 or 5.0 mg to 6.25 mg of hydrochlorothiazide per day, has additive effects that are effective in controlling blood pressure, whether mild, moderate or severe, and that helps hypertensive patients to achieve the control goals at a very high percentage and in the short term, without affecting other systems so they are safe in hypertensive diabetic and dyslipidemic patients, and in conjunction with the heart rate regulation provides cardio-protection to patients at high cardiovascular risk. Fixed combinations of antihypertensive drugs simplify dosing regimen, improve adherence to treatment, hypertension control, decrease dose-dependent adverse effects and decrease costs as a first line treatment for hypertension.
... Cruickshank suggests that the ISA on the b2 and the b3 receptors is responsible for the reduction of effect on heart failure with nebivolol. 40 ...
Beta-adrenergic receptor blockers or β-blockers represent one of the oldest classes of cardiovascular agents and have been considered as a cornerstone therapy for hypertension and heart disease for the last 5 decades. They are advocated as a first-line treatment for uncomplicated essential hypertension in patients less than 60 years of age as recommended by the Canadian Hypertension Education Program (CHEP). However, despite the well-established antihypertensive and cardiovascular benefits of β-blockers, a number of studies argue that they may not have the same clinical advantages of other classes of agents in terms of morbidity/mortality outcomes. The paper will focus on the heterogeneity of the pharmacologic characteristics of β-blockers discussing the metabolic and hemodynamic differences within the β-blocker class and try to assess the potential implications of these differences for optimal selection in hypertension.
... A.Beta-blockers – scientific support according to the studies cited in the guidelines [16-21]. ...
Rationale: Cardiac risk in patients undergoing surgery depends on many factors from the patient's cardiovascular history to the surgical procedure itself, with its particularities, the type of anesthesia, fluid exchanges and the supervision of the patient. Therefore, this risk must be carefully considered and it determines the endorsement of perioperative measures with important medical implications. Objective: Perioperative cardiac risk evaluation guidelines were published since 2010 and they represent a highly important assessmnet tool. Emergency surgery requires an adaptation of the guidelines to the actual medical situations in extreme conditions.
Methods, Results, Discussion: Analyzing the way the perioperative evaluation itself is conducted is an extremely important tool. Quantifying the clinical application of the guidelines, one can monitor real parameters and find solutions for improving medical care. The current study was conducted on a representative sample of 8326 patients, respecting the recommendation strategies for calculating the surgical risk adapted for the emergency surgery setting. The dominant conclusion is the need to develop a standardized form, summarized for quick and objective assessment of perioperative cardiac risk score. Only a complex medical team could calculate this score while the decisional team leader for the surgical patient remains the surgeon.
... Reductions in heart rate lead to restoration of the myocardial ,oxygen supply-demand balance and prolongation of coronary diastolic filling time [10], which is of benefit to the surgical patient with a compromised coronary circulation exposed to the stress of surgery. Ivabradine was as effective as β-blockers at preventing the perioperative incidence of the primary endpoint, a composite of all-cause mortality and nonfatal MI. ...
The benefits of improved clinical outcomes through blood pressure (BP) reduction have been proven in multiple clinical trials and meta-analyses. The new (2023) guideline from the European Society of Hypertension (ESH) includes β-blockers within five main classes of antihypertensive agents suitable for initiation of antihypertensive pharmacotherapy and for combination with other antihypertensive agents. This is in contrast to the 2018 edition of ESH guidelines that recommended β-blockers for use primarily in patients with compelling indications such as cardiovascular comorbidities, e.g. coronary heart disease, heart failure. This change was based on the fact that the magnitude of BP reduction is the most important factor for adverse cardiovascular outcomes, over and above the precise manner in which reduced BP is achieved. The ESH guideline also supports the use of β-blockers for patients with resting heart rate (>80 bpm); high resting heart rate is a sign of sympathetic overactivity, an important driver of adverse cardiac remodelling in the setting of hypertension and heart failure. Hypertension management guidelines support for the use of combination therapies for almost all patients with hypertension, ideally within a single-pill combination to optimise adherence to therapy. Where a β-blocker is prescribed, the inclusion of a dihydropyridine calcium channel blocker within a combination regimen is rational. These agents together reduce both peripheral and central BP, which epidemiological studies have shown is important for reducing the burden of premature morbidity and mortality associated with uncontrolled hypertension, especially strokes.
β-blockers are a heterogeneous class, with individual agents distinguished by selectivity for β1- vs. β2- and α-adrenoceptors, presence or absence of partial agonist activity at one of more β-receptor subtype, presence or absence of additional vasodilatory properties, and lipophilicity, which determines the ease of entry the drug into the central nervous system. Cardioselectivity (β1-adrenoceptor selectivity) helps to reduce the potential for adverse effects mediated by blockade of β2-adrenoceptors outside the myocardium, such as cold extremities, erectile dysfunction, or exacerbation of asthma or chronic obstructive pulmonary disease. According to recently updated guidelines from the European Society of Hypertension, β-blockers are included within the five major drug classes recommended as the basis of antihypertensive treatment strategies. Adding a β-blocker to another agent with a complementary mechanism may provide a rational antihypertensive combination that minimizes the adverse impact of induced sympathetic overactivity for optimal blood pressure-lowering efficacy and clinical outcomes benefit.
Arterial hypertension in young adults is not well defined due to the high variability of the corresponding age interval. However, ages 18 through 45 seem to be the most reasonable based on common pathogenic mechanisms like sympathetic overactivity and a particular influence of obesity. In young individuals, essential hypertension in general and isolated systolic hypertension in particular are the most common forms of hypertension though secondary hypertension is more common when compared to older adults, particularly in the setting of severe hypertension, endocrinopathy, or chronic kidney disease. Hypertension awareness and blood pressure control rates are the lowest among young adults, despite risk assessment models underestimating cardiovascular risk in this category of patients due to an increased likelihood of lifetime cardiovascular events. Lifestyle interventions are considered first-line treatment, and pharmacologic treatment should be aimed at lowering the overactivity of the sympathetic nervous and renin-angiotensin-aldosterone systems through ACEi and beta-blockers without sympathomimetic activity. Particularities of antihypertensive treatment in athletes and pregnancy are also discussed.
Asthma has been recognised as a respiratory disorder for millennia and the focus of targeted drug development for the last 120 years. Asthma is one of the most common chronic non-communicable diseases worldwide. Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide, is caused by exposure to tobacco smoke and other noxious particles and exerts a substantial economic and social burden. This chapter reviews the development of the treatments of asthma and COPD particularly focussing on the β-agonists, from the isolation of adrenaline, through the development of generations of short- and long-acting β-agonists. It reviews asthma death epidemics, considers the intrinsic efficacy of clinical compounds, and charts the improvement in selectivity and duration of action that has led to our current medications. Important β2-agonist compounds no longer used are considered, including some with additional properties, and how the different pharmacological properties of current β2-agonists underpin their different places in treatment guidelines. Finally, it concludes with a look forward to future developments that could improve the β-agonists still further, including extending their availability to areas of the world with less readily accessible healthcare.
Known off-target interactions frequently cause predictable drug side-effects (e.g., β1-antagonists used for heart disease, risk β2-mediated bronchospasm). Computer-aided drug design would improve if the structural basis of existing drug selectivity was understood. A mutagenesis approach determined the ligand-amino acid interactions required for β1-selective affinity of xamoterol and nebivolol, followed by computer-based modeling to provide possible structural explanations. 3H-CGP12177 whole cell binding was conducted in Chinese hamster ovary cells stably expressing human β1, β2, and chimeric β1/β2-adrenoceptors (ARs). Single point mutations were investigated in transiently transfected cells. Modeling studies involved docking ligands into three-dimensional receptor structures and performing molecular dynamics simulations, comparing interaction frequencies between apo and holo structures of β1 and β2-ARs. From these observations, an ICI89406 derivative was investigated that gave further insights into selectivity. Stable cell line studies determined that transmembrane 2 was crucial for the β1-selective affinity of xamoterol and nebivolol. Single point mutations determined that the β1-AR isoleucine (I118) rather than the β2 histidine (H93) explained selectivity. Studies of other β1-ligands found I118 was important for ICI89406 selective affinity but not that for betaxolol, bisoprolol, or esmolol. Modeling studies suggested that the interaction energies and solvation of β1-I118 and β2-H93 are factors determining selectivity of xamoterol and ICI89406. ICI89406 without its phenyl group loses its high β1-AR affinity, resulting in the same affinity as for the β2-AR. The human β1-AR residue I118 is crucial for the β1-selective affinity of xamoterol, nebivolol, and ICI89406 but not all β1-selective compounds. SIGNIFICANCE STATEMENT: Some ligands have selective binding affinity for the human β1 versus the β2-adrenoceptor; however, the molecular/structural reason for this is not known. The transmembrane 2 residue isoleucine I118 is responsible for the selective β1-binding of xamoterol, nebivolol, and ICI89406 but does not explain the selective β1-binding of betaxolol, bisoprolol, or esmolol. Understanding the structural basis of selectivity is important to improve computer-aided ligand design, and targeting I118 in β1-adrenoceptors is likely to increase β1-selectivity of drugs.
Diseases of the cardiovascular system have been the biggest cause of mortality for the majority of the last century, currently contributing to almost a third of deaths every year globally. Ageing associates with changes to the structure and function of the heart and vascular system that progressively increase the incidence of abnormalities, morbidity, and cardiovascular disease. The burden of ageing and its relationship to cardiovascular disease risk highlights the need for more research into the underlying mechanisms involved and how they may be treated and/or prevented. Factors influencing adrenergic dysfunction may explain a significant part of the age-related deterioration in health and responsiveness of the cardiovascular system. Increased sympathetic activity in old age overstimulates adrenergic receptors and causes detrimental changes within the associated signalling mechanisms including a reduction in receptor number and downstream effector efficiency. Pharmacological agents such as metformin, resveratrol, beta-blockers, and angiotensin converting enzyme (ACE) inhibitors have been identified as potential anti-ageing therapies with cardiovascular effects, which may be beneficial in treating the decline in cardiovascular function with old age. Regular exercise has also shown promise in the prevention and treatment of harmful age-related effects on the cardiovascular system. This review will investigate age-associated vascular and cardiac remodelling, and the link between adrenergic dysfunction and vascular and cardiac control. This review will also consider whether pharmacological or non-pharmacological therapies are most effective, or indeed complimentary to potentially optimise ageing of the cardiovascular system and improve quality of life in the elderly.
Beta‐blocker overdose is potentially harmful due to the strong blood pressure‐lowering and heart rate‐lowering effect. However, conflicting data exist as to their differential toxicity, single‐substance exposures, and the effect of co‐exposure with additional antihypertensive medication. For this, a 10‐year retrospective, explorative analysis of the Mainz Poison Center/Germany database with regard to circumstances of beta‐blocker exposure, doses, symptoms and treatment was carried out. Analyses were restricted to adult patients with single‐substance exposures and co‐exposures with one additional antihypertensive substance. Written follow‐up information was obtained in half the cases. A total of 2967 cases were analysed, of which 697 were single‐substance exposures. Metoprolol was most frequently reported followed by bisoprolol, atenolol, propranolol and sotalol. Metoprolol showed a linear dose‐symptom relationship, whereas propranolol and sotalol seemed to have a threshold dose beyond which symptoms aggravated. Symptoms did not differ substantially, except for more seizures being reported with propranolol, and more CNS depression/vomiting with sotalol. Activated charcoal was used in 38%, gastric lavage in 11%, temporary pacemaker in 3%, glucagon in 1%, intubation for respiratory insufficiency and cardiopulmonary resuscitation in 1% and 0.5%. All patients recovered. In 174 co‐exposure cases, the distribution of poisoning severity and rate of worsening of symptoms was comparable with single‐substance exposures except one patient deceased after bisoprolol and verapamil co‐exposure. In adults with beta‐blocker overdose, no significant differences in poisoning severity among beta‐blockers were detected, and no fatalities were observed with single‐substance exposures. Co‐exposures with other antihypertensives, sedatives or alcohol should be carefully attended to as fatalities might occur.
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Background:
It is crucial to understand the pharmacological differences between the effects of beta blockers on the lipid and glucose profile. Moreover, the management of lipid and glucose profile is essential in cardiovascular patients.
Objective:
We sought to compare two beta blockers, metoprolol and bisoprolol, as the most commonly used drugs in cardiology in terms of their effects on glucose and lipid profiles in patients with cardiovascular diseases.
Methods:
We conducted a retrospective cross-sectional matched study at Prince Sultan Cardiac Center in Burydah in May 2018. Patient records were screened, and adult patients with cardiovascular disorders who were treated with a stable dose of metoprolol or bisoprolol were included. Parameters related to glucose and lipid metabolism were compared using the Student's t-test between the two groups.
Results:
The metoprolol arm included 204 patients and the bisoprolol arm included 200 patients. There was no significant difference in the baseline characteristics between the two arms. Mean patient age in the metoprolol arm was 58.8 years, whereas it was 58.1 years in the bisoprolol arm. The most common dose of bisoprolol was 5 mg OD (85% patients), whereas that of metoprolol was 50 mg BID (86% patients). There was a significant difference in triglyceride levels between the groups with a mean difference of 0.401 and a CI of 0.102-0.703. There were no significant differences in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and Hb1Ac levels. Besides, there was no significant difference in the incidence of diabetes mellitus between patients treated with metoprolol and bisoprolol (P=0.316).
Conclusion:
Bisoprolol may increase serum triglyceride level to a greater extent than metoprolol. Nevertheless, the two drugs similarly affect glucose and lipid profiles in patients with cardiovascular diseases.
The study objective was to compare the long-term incidence and risk of mortality and cardiovascular outcomes in patients with hypertension initiating bisoprolol, other β-blockers or other antihypertensive therapies. Cohort analysis using UK Clinical Practice Research Datalink (CPRD). Adult patients with first diagnosis of hypertension recorded between 2000-2014, with ≥365 days of registration to first event and initiating monotherapies of bisoprolol, other β-blockers or drugs other than β-blockers within 6 months of diagnosis were included. Incidence rates (IR) for each treatment cohort were compared using adjusted hazard ratio (HR) and 95% confidence intervals (CI) obtained from Cox regression analyses. Of 100,066 patients included, 539 were prescribed bisoprolol, 3,701 other β-blockers, and 95,826 drugs other than β-blockers. Patients receiving bisoprolol had significantly increased survival from 2 up to <15 years (HR for <15 years 0.34; 95% CI 0.18-0.67) versus other β-blockers, and from 5 to <15 years (HR for <15 years 0.52; 95% CI 0.27-1.00) versus drugs other than β-blockers. Over time, the risk of arrhythmia was higher in the bisoprolol cohort versus other β-blockers, and risks of arrhythmia and angina were higher versus drugs other than β-blockers. No differences in the risk of embolism, stroke, and MI were found between cohorts. Over time, mortality and cardiovascular outcome IRs decreased in each cohort. In conclusion, bisoprolol showed sustained benefit on survival, evident from 2 years after treatment initiation versus other β-blockers, and from 5 years versus drugs other than β-blockers, providing long-term evidence supporting the use of bisoprolol in patients with hypertension in primary care.
The role of beta-adrenoceptor antagonists (beta-blockers) in cardiovascular therapy has been subject to diverse trends and changes over the decades. With the advent of a wide variety of excellent drugs for the treatment of antihypertension, beta-blockers have been relegated from the first-line treatment of essential hypertension. However, they remain the drugs of first choice in recommendations from the respective medical societies for heart failure, coronary artery disease, and atrial fibrillation as well as in hypertension complicated with heart failure, angina pectoris, or prior myocardial infarction. When indicated, cardioselective ?-blockers should be prescribed in patients with diabetes mellitus or chronic obstructive pulmonary disease. We review the available evidence for the use of ?-blockers in clinical conditions in which recommendations can be made for everyday practice.
Treating people with cardiovascular disease and COPD causes significant clinician anxiety. β-Blockers save lives in people with heart disease, specifically postinfarction and heart failure. COPD and heart disease frequently coexist and people with both disorders have particularly high cardiovascular mortality. There are concerns about giving β-blockers to people with concomitant COPD that include reduced basal lung function, diminished effectiveness of emergency β-agonist treatments, reduced benefit of long-acting β-agonist treatment and difficulty in discriminating between asthma and COPD. β-Blockers appear to reduce lung function in both the general population and those with COPD because they are poorly selective for cardiac β1-adrenoceptors over respiratory β2-adrenoceptors, and studies have shown that higher β-agonist doses are required to overcome the β-blockade. COPD and cardiovascular disease share similar environmental risks and both disease states have high adrenergic and inflammatory activation. β-Blockers may therefore be particularly helpful in reducing cardiovascular events in this high-risk group. They may reduce the background inflammatory state, and inhibit the tachycardia and hypertension associated with both the endogenous adrenaline and high-dose β-agonist treatment associated with acute exacerbations of COPD. Some studies have suggested no increased and, at times, reduced mortality in patients with COPD taking β-blockers for heart disease. However, these are all observational studies and there are no randomised controlled trials. Potential ways to improve this dilemma include the development of highly β1-selective β-blockers or the use of non-β-blocking heart rate reducing agents, such as ivabridine, if these are proven to be beneficial in randomised controlled trials.
OBJECTIVE: To provide an up-to-date review of the available evidence regarding treatment of acute coronary syndromes (ACS) in elderly patients.
DATA SOURCE: A PubMed search of articles published through January 2015 was done using a combination of the following words: acute coronary syndrome, pharmacy, elderly, geriatric, myocardial infarction, beta-blocker, statin, antiplatelet, antithrombin, angiotensin-converting enzyme inhibitor, and aspirin.
STUDY SELECTION/DATA EXTRACTION: Relevant original research, review articles, and guidelines were assessed for the management of elderly patients with ACS. References from the above literature were also evaluated. Articles were selected for inclusion based on relevance to the topic, detailed methods, and complete results.
DATA SYNTHESIS: Because of the high prevalence of ACS in elderly patients, appropriate treatment is necessary to reduce morbidity and mortality; however, these patients are often under-represented in trials. This article provides a review of the current literature on treatment of ACS in the elderly and provides guidance to pharmacists regarding optimal pharmacotherapy for these patients.
CONCLUSION: Appropriate treatment of ACS can help improve outcomes in elderly patients, and the pharmacist can provide guidance regarding evidence-based therapy.
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and it increases the risk of thromboembolic stroke and death. AF is common in patients with heart failure and reduced ejection fraction (HFrEF), affecting between 30 and 40% of patients with HFrEF. AF increases the risk of death and hospitalization in patients with HFrEF. Only two antiarrhythmic drugs (amiodarone and dofetilide) are guideline-recommended in patients with AF and heart failure (HF). Meta-analyses of studies of major trials in HF suggest that patients with AF/HFrEF do not benefit from conventional β-blockers. Bucindolol has shown promise in the treatment of patients with AF/HFrEF. We will explore how the shared pathophysiology of AF/HF is targeted by the unique pharmacology of bucindolol and review the existing data for bucindolol in AF/HF. We will explore findings that support a pharmacogenetically modulated effect of bucindolol in patients with polymorphisms in β1-adrenergic receptor and provide an overview of ongoing studies.
This review is focused on the influence of salicylates as well as preparations used for the treatment of obesity, diabetes mellitus, arterial hypertension, and atherosclerosis on the functional state of the adipose tissue and the inflammatory processes affecting it. Many of these medicines show the anti-inflammatory activity mediated through a variety of mechanisms. There is thus far no medicamental preparations for the specific treatment of adipose tissue inflammation. Nevertheless, the anti-inflammatory action of certain drugs should be taken into consideration when they are prescribed for the treatment of clinical conditions with concomitant obesity and suspicion of inflammation of the adipose tissue.
Adrenergic β-receptor antagonists have been one of the most important discoveries in cardiovascular medicine in the last 50 years. The first β-blocker was synthesized in the 1960s, and since then a very heterogeneous class of drugs (differing in β-adrenergic receptor selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity, and vasodilatory capabilities) was found. No other class of drugs has demonstrated such a widespread therapeutic utility for the treatment and prevention of so many manifestations of cardiovascular disorders. Currently, the key uses of β-blockers are as antihypertensive and antianginal agents, as first-line treatment for rate control in patients with atrial fibrillation, and as drugs that reduce morbidity and mortality after myocardial infarction and in heart failure. Since many other cardiovascular therapies have been developed over the last few years, it is questionable whether the role of β-blockers in this era of the multidrug approach still resonates for the management of cardiovascular diseases.
Purpose of review:
The most common and significant morbidity and mortality of vascular surgical procedures remain coronary artery disease, arrhythmia, and heart failure. Cardiac evaluation and medical optimization provide the groundwork for best medical practice in an otherwise high-risk surgical population. The goal of this study is to review the most current literature and guidelines for evaluating patients prior to vascular surgical interventions. From this, we have made our own recommendations regarding both the preoperative and perioperative management of vascular surgical patients.
Recent findings:
Risk stratification using a modified Lee index may be best to assess perioperative cardiac risk. Coronary revascularization should be reserved for those patients with significant coronary disease irrespective of symptoms. β-blockers, statins, and antiplatelet agents should be considered for all patients with peripheral vascular disease.
Summary:
The preoperative management of vascular surgical patients requires a complete understanding of the patient's medical history as it relates to their perioperative cardiac risk. Overwhelming data support the use of medical therapy as adjunct to minimize or prevent the risk of future cardiovascular events. As vascular surgery transitions to the outpatient setting, further studies will be required to better elucidate cardiac evaluation in this patient population.
Central obesity is closely linked to hypertension and type-2 diabetes (DM2) in young/middle-age. In the elderly, systolic hypertension is a reflection of aging/stiff arteries. Diastolic (±systolic) hypertension in young/middle-age is accompanied by increased sympathetic nerve activity, particularly in the presence of the metabolic syndrome or DM2. High beta-receptor density (Bmax) and cyclic AMP (cAMP) levels in human lymphoctes, independent of blood pressure, are associated with a high risk of myocardial infarction (not stroke-risk, which is dependent on blood pressure). This has treatment implications in the young/middle-aged hypertensive subject. Antihypertensive agents that increase sympathetic nerve activity e.g. dihydropyridine calcium blockers, angiotensin receptor blockers, and thiazide-type diuretics, do not reduce (and may increase) the risk of myocardial infarction. Beta-1 blockade, effective in reversing and stabilising coronary atheromataous plaque, and with possible anti-tumor properties, is superior to ACE-inhibition, and is the treatment of choice in young/middle-aged hypertension with DM2.
Betablockers are extensively used but have been recently questioned about their perioperative administration when patients are susceptible to experience unstable haemodynamic condition. Betabloquers impair the efficacy of fluid infusion to treat hypovolemia. Betablockers reverse the effects of epinephrine while the impact on dobutamine effects varies depending on the agent administered. Phenyleprine administration may lead to acute cardiac failure by uncompensated stimulation of alpha1 adrenergic receptors. No significant interaction is documented between betablockers and phosphodiesterase inhibitors and levosimendan. Glucagon may be used in betablocked patients suffering from anaphylactic shock. Betablocker intoxication may be treated by high doses of insulin coupled with potassium and glucose administration.
Context. Hypertensive patients are often given a calcium antagonist to reduce cardio-vascular disease risk, but the benefit compared with other drug classes is controversial.
Objective. To determine whether initial therapy with controlled-onset extended-
release (COER) verapamil is equivalent to a physician’s choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease.
Design, Setting, and Participants. Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed
the study before unblinding the results.
Intervention. Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed.
Main Outcome Measures. First occurrence of stroke, myocardial infarction, or cardiovascular disease–related death.
Results. Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 nomm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease–related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P=.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease–related death, 1.09 (95% CI,
0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease–related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Non-stroke hemorrhage was more common with participants in the COER-verapamil group (n=118) compared with the atenolol or hydrochlorothiazide group (n=79) (HR, 1.54[95% CI, 1.16-2.04]; P=.003). More cardiovascular disease–related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53).
Conclusions. The CONVINCE trial did not demonstrate equivalence of a COER verapamil–based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or �beta-blocker treatment.
On page 30, right hand column, line 7 should read:
and the percentage reduction in infarct size
and not:
and the percentage reduction in heart size
and line 13 should read:
ated with a non-significant increase in the infarct
and not:
ated with a non-significant decrease in the infarct
Background
Central aortic systolic blood pressure (BP) is an important determinant of cardiac workload and cardiac hypertrophy. The relationship of central aortic systolic BP and brachial BP varies depending on the stiffness of blood vessels. It is not certain whether the different drug classes affect the brachial and aortic systolic BP in a similar manner.
Methods
In a double-blind crossover study, we measured the effects of the four major drug classes compared with placebo on central aortic pressure. Central aortic pressure and various indices were determined using the Sphygmo Cor apparatus. The study was undertaken in patients aged 65 to 85 years with systolic BP >150 mm Hg at study entry. Results are reported for 32 patients who had satisfactory applanation tonometry in all five periods.
Results
Calcium channel blockers and diuretics caused a greater fall in brachial artery systolic BP than angiotensin-converting enzyme (ACE) inhibitors or β-blocking drugs. On placebo, central aorta augmentation pressure and index were 23 mm Hg and 33.3%; on ACE inhibitors the values were 18 mm Hg and 30%; on β-blockers, 26 mm Hg and 38.5%; on calcium channel blockers, 16 mm Hg and 28%; and on diuretics, 17 mm Hg and 28.8%. The augmentation pressure on β-blocking drugs was greater than on the other three drug classes (P < .05), and augmentation pressures on ACE inhibitors, calcium channel blockers, and diuretics were less than on placebo (P < .05). The lowest central aortic pressures were achieved with calcium blocking drugs and diuretics.
Conclusions
Therapy based on brachial artery recordings may thus overestimate the effect of β-blocking drugs on central aortic systolic BP and underestimate the effectiveness of ACE inhibitors and calcium blocking drugs. The clinical importance of this discrepancy needs to be evaluated.
Am J Hypertens 2004;17:118–123 © 2004 American Journal of Hypertension, Ltd.
Background
Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension.
Methods
18 790 patients, from 26 countries, aged 50–80 years (mean 61·5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure ⩽90 mm Hg, 6264 to ⩽85 mm Hg, and 6262 to ⩽80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo.
Findings
Diastolic blood pressure was reduced by 20·3 mm Hg, 22·3 mm Hg, and 24·3 mm Hg, in the ⩽90 mm Hg, ⩽85 mm Hg, and ⩽80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82·6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86·5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group ⩽80 mm Hg compared with target group ⩽90 mm Hg (p for trend=0·005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0·03) and all myocardial infarction by 36% (p=0·002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0·001).
Interpretation
Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82·6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.
The effect of metoprolol on mortality and morbidity after 15 days, was compared with that of placebo in a double-blind randomised international trial (the MIAMI trial) in patients with definite or suspected acute myocardial infarction (AMI). Treatment with intravenous metoprolol (15mg) or placebo was started shortly after the patient's arrival in hospital within 24 h of the onset of symptoms, and then oral treatment (200 mg daily) was continued for the study period (15 days). Of the 5778 patients included, 2901 were allocated to placebo and 2877 to metoprolol. Definite AMI was confirmed in 4127 patients. There were 142 deaths in the placebo group (4.9%) and 123 deaths in the metoprolol group (4.3%), a difference of 13 per cent with 95 per cent confidence limits of −8 to +33 per cent, not statistically significant (P=0.29).
Previously recorded risk indicators of mortality were analysed in retrospect. These indicated that there was a category which showed higher risk which contained approximately 30% of all randomized patients. In these, the mortality rate in the metoprolol treated group was 29% less than in the placebo group. In the remaining lower risk categories there was no difference between the treatment groups. This subset analysis must be interpreted with caution in view of the findings from other similar studies.
Positive effects were observed on the incidence of definite AMI and on serum enzyme activity in patients treated early ( <7h). There was no significant effect on ventricular fibrillation but the number of episodes tended to be lower in the metoprolol treated patients during the later phase (6–15 days; 24 vs 54 episodes). The incidence of supraventricular tachyarrhythmias, the use of cardiac glycosides and other antiarrhythmics, and the need for pain-relieving treatment were significantly diminished by metoprolol amongst all randomised patients. Adverse events associated with metoprolol were infrequent, expected, and relatively mild.
Seventeen thousand three hundred and fifty four mildly hypertensive people with diastolic blood pressures between 90 and 109 mm Hg at screening were randomised to active treatment, with bendrofluazide or propranolol, or to placebo tablets. They were followed for a maximum of five and a half years, giving a total of 85 572 patient-years of observation. There were 456 myocardial infarctions or sudden coronary deaths. Drug treatment did not affect the overall rate ofcoronary events. Rates per thousand person-years were 8.3 and 9.0 in men and 1.8 and 1.7 in women in the active treatment and placebo groups respectively. Event rates were much higher in smokers than in non-smokers on placebo treatment (12.6 and 7.5 in men and 3.5 and 1 0 in women in smokers and non-smokers respectively). An analysis of subgroup results showed a lower event rate in non-smoking men on propranolol than in non-smokers on placebo (5.0 and 7.5 per thousand person-years respectively). Bendrofluazide had no apparent effect on the event rate. The interaction between the type oftreatment (propranolol, bendrofluazide, or placebo) and smoking in determining the coronary event rate was not statistically significant, however. The incidence of electrocardiographic changes of silent infarction-that is major Q/QS abnormalities-differed little with sex, smoking habit, or treatment with either active drug.
The effect of metoprolol on mortality and morbidity after 15 days, was compared with that of placebo in a double-blind randomised international trial (the MIAMI trial) in patients with definite or suspected acute myocardial infarction (AMI). Treatment with intravenous metoprolol (15 mg) or placebo was started shortly after the patient's arrival in hospital within 24 h of the onset of symptoms, and then oral treatment (200 mg daily) was continued for the study period (15 days). Of the 5778 patients included, 2901 were allocated to placebo and 2877 to metoprolol. Definite AMI was confirmed in 4127 patients. There were 142 deaths in the placebo group (4.9%) and 123 deaths in the metoprolol group (4.3%), a difference of 13 per cent with 95 per cent confidence limits of -8 to +33 per cent, not statistically significant (P=0.29). Previously recorded risk indicators of mortality were analysed in retrospect. These indicated that there was a category which showed higher risk which contained approximately 30% of all randomized patients. In these, the mortality rate in the metoprolol treated group was 29% less than in the placebo group. In the remaining lower risk categories there was no difference between the treatment groups. This subset analysis must be interpreted with caution in view of the findings from other similar studies. Positive effects were observed on the incidence of definite AMI and on serum enzyme activity in patients treated early (<7 h). There was no significant effect on ventricular fibrillation but the number of episodes tended to be lower in the metoprolol treated patients during the later phase (6-15 days; 24 vs 54 episodes). The incidence of supraventricular tachyarrhythmias, the use of cardiac glycosides and other antiarrhythmias, and the need for pain-relieving treatment were significantly diminished by metoprolol amongst all randomised patients. Adverse events associated with metoprolol were infrequent, expected, and relatively mild.
Objective - To establish whether treatment with diuretic or β blocker in hypertensive older adults reduces risk of stroke, coronary heart disease, and death. Design - Randomised, placebo controlled, single blind trial. Setting - 226 general practices in the MRC general practice research framework. Subjects - 4,396 patients aged 65-74 randomised to receive diuretic, β blocker, or placebo. Patients had mean systolic pressures of 160-209 mm Hg and mean diastolic pressures <115 mm Hg during an eight week run in and were not taking antihypertensive treatment. Intervention - Patients were randomised to atenolol 50 mg daily; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily; or placebo. The regimens were adjusted to achieve specified target pressures. Mean follow up was 5.8 years. Main outcome measures - Strokes, coronary events, and deaths from all causes. Results - Both treatments reduced blood pressure below the level in the placebo group. Compared with the placebo group, actively treated subjects (diuretic and β blocker groups combined) had a 25% (95% confidence interval 3% to 42%) reduction in stroke (p = 0.04), 19% (-2% to 36%) reduction in coronary events (p = 0.08), and 17% (2% to 29%) reduction in all cardiovascular events (p = 0.03). After adjusting for baseline characteristics the diuretic group had significantly reduced risks of stroke (31% (3% to 51%) p = 0.04), coronary events (44% (21% to 60%), p = 0.0009), and all cardiovascular events (35% (17% to 49%), p = 0.0005) compared with the placebo group. The β blocker group showed no significant reductions in these end points. The reduction in strokes was mainly in non-smokers taking the diuretic. Conclusion - Hydrochlorothiazide and amiloride reduce the risk of stroke, coronary events, and all cardiovascular events in older hypertensive adults.
Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial. We aimed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris. METHODS: We randomly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS (gastrointestinal therapeutic system) 60 mg once daily and 3840 to placebo. The primary endpoint was the combination of death, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularisation. Mean follow-up was 4.9 years (SD 1.1). Analysis was by intention to treat. FINDINGS: 310 patients allocated nifedipine died (1.64 per 100 patient-years) compared with 291 people allocated placebo (1.53 per 100 patient-years; hazard ratio 1.07 [95% CI 0.91-1.25], p=0.41). Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo (0.97 [0.88-1.07], p=0.54). With nifedipine, rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo (0.89 [0.83-0.95], p=0.0012). The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine, despite an increase in peripheral revascularisation. Nifedipine had no effect on the rate of myocardial infarction. INTERPRETATION: Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival. Nifedipine GITS is safe and reduces the need for coronary angiography and interventions.
Background and purpose:
beta-Blockers prevent vascular events in patients after myocardial infarction and lower blood pressure, the main risk factor for stroke. Hence, we assessed the effects of atenolol on the occurrence of death from vascular causes, stroke, or myocardial infarction and on blood pressure in patients after a transient ischemic attack or nondisabling ischemic stroke.
Methods:
In a double-blind, placebo-controlled randomized clinical trial we studied the occurrence of the outcome event death from vascular causes, nonfatal stroke, or nonfatal myocardial infarction and the outcome event fatal or nonfatal stroke as well as blood pressure on follow-up. A total of 1,473 aspirin-treated patients with transient ischemic attack or nondisabling ischemic stroke were randomized to 50 mg atenolol daily or placebo. The mean follow-up was 2.6 years.
Results:
Patients on atenolol had a risk of 97/732 (13.3%) for the combined outcome event versus a risk of 95/741 (12.8%) for those on placebo (adjusted hazard ratio, 1.00; 95% confidence interval, 0.76-1.33). The adjusted hazard ratio for fatal or nonfatal stroke was 0.82 (95% confidence interval, 0.57-1.19). More patients on beta-blocker (153) reported adverse effects than on placebo (103). At the first follow-up visit after randomization (median at 4 months) systolic blood pressure in the atenolol group had dropped by 8.0 mm Hg compared with 2.2 mm Hg in the placebo group (difference, 5.8 mm Hg; 95% confidence interval, 2.9-8.6 mm Hg). For diastolic blood pressure this difference was 2.9 mm Hg (95% confidence interval, 1.5-4.4 mm Hg).
Conclusions:
Our data neither confirm nor rule out that atenolol prevents important vascular events in patients after transient ischemic attack or nondisabling ischemic stroke, given the modest effect on blood pressure, the restrictions in patient selection, and the limited number of patient-years.
Bisoprolol is a relatively newly developed, highly β1-adrenoceptor-selective antagonist. Radioligand binding studies using tissues of several species, including humans, have revealed that the affinity of bisoprolol for β1-adrenoceptors is at least 20-fold, and up to 100-fold, higher than its affinity for β2-adrenoceptors. A similar high degree of β1-adrenoceptor selectivity has been demonstrated also in in vitro organ bath studies employing various tissue preparations from several species, including humans, as well as in vivo. Bisoprolol does not exert any intrinsic sympathomimetic activity. Its haemodynamic effects are those that can be expected from β-adrenoceptor blockade: heart rate is reduced at rest and during exercise, cardiac output falls, and there is a slight tendency for peripheral resistance to increase, at least initially. Bisoprolol is (at least in the therapeutically recommended doses of 5 mg and 10 mg) nearly devoid of any β2-adrenoceptor antagonistic activity, and it has therefore no effects on β2-adrenoceptor mediated metabolic effects, such as hyperglycaemia or hypokalaemia.
The property of β1-selectivity leads to differences among β-blockers with respect to their haemodynamic, metabolic and respiratory effects. Most of the therapeutically desirable actions of β-blockers are based upon blocking the β1- receptor. Avoiding β2-mediated reactions should help to avoid undesired drug reactions. From the haemodynamic point of view, it is notable that β1-selective drugs may produce a greater reduction in diastolic blood pressure. In addition, β1-selective drugs are less likely to increase total peripheral flow resistance compared to nonselective drugs as no, or less, vasoconstriction caused by β2-blockade is to be expected. This latter will be advantageous in treating patients who suffer from peripheral vascular disease. An increase in total cholesterol or LDL-cholesterol and the triglycerides, as well as a decrease in HDL-cholesterol, are related to a blockade of β2-receptors. These changes are less apparent with a β1-selective drug such as the highly β1-selective bisoprolol. Unlike nonselective agents, β1-selective β-blockers are less likely to influence carbohydrate metabolism and do not prolong insulin-induced hypoglycaemia. Due to the relative preservation of β2-bronchodilatory action, a β1-selective compound will generally not cause bronchospasm in predisposed patients, such as those suffering from asthma bronchiale or chronic obstructive lung disease. The β2-sympathomimetic action of β2-stimulants such as salbutamol or isoprenaline will be preserved. In cases in which a β-blocker is required a β1-selective drug should be selected. The higher its β1-selectivity, the less likely are β2-mediated adverse effects to occur.
Background: There is strengthening evidence that essential hypertension is commonly neurogenic, initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex dampening of sympathetic nerve traffic and sympathetic neuromodulation by angiotensin II. Methods and results: To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin-sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac 3[H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin ii plasma concentrations were similar in both groups and were not related to indices of sympathetic activation. Conclusions: Increased rates of sympathetic nerve firing and reduced neuronal ne reuptake both contribute to sympathetic activation in hypertension, whereas a role for dampened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin ii seem to be excluded.
The Australian therapeutic trial in mild hypertension, which was undertaken to investigate the value of pharmacological treatment, showed significant benefit in treated subjects. The control (placebo) group in this study comprised 1943 persons with mild hypertension who were not given antihypertensive drug treatment. They had regular visits for measurements of blood-pressure and were evaluated at intervals to detect the occurrence of trial end-points (essentially cardiovascular or cerebrovascular events). This paper reports the changes in blood-pressure and occurrence of trial end-points in these untreated subjects who entered the study between June, 1973, and December, 1975; observations were made up to March, 1979. In all subjects of the Australian therapeutic trial in mild hypertension, mean pressures for the two screening visits were within the range 95-109 mm Hg for diastolic blood-pressure phase V (DBP) and <200 mm Hg for systolic blood-pressure (SBP). In the 1943 control (placebo) subjects mean blood-pressures fell from 158/102 mm Hg at the first screening visit to 144/91 mm Hg 3 years later. At that time pressures remained within the mild hypertension range in 32%, had risen above it in 12%, and had fallen below in 48%. Trial end-points (ischaemic heart disease or cerebrovascular accident) occurred in 8%. The outcome was related to the level of initial pressure but not to other characteristics measured at entry. The mean initial pressures of 22 subjects who experienced a cerebrovascular event were higher than those of a matched group with no hypertensive complications, but the 88 subjects who experienced ischaemic-heart-disease events had initial pressures similar to those in a matched control group. The trial end-point was related to the average DBP of subjects throughout the trial in those with average DBP ≥95 mm Hg, and at those levels subjects on active treatment had a higher incidence than subjects of the placebo group with the same DBP level. For those with average DBP below 95 mm Hg the incidence of trial end-points was not related to blood-pressure level or treatment. 16% of placebo subjects in this mild hypertensive population had a mean DBP of less than 95 mm Hg at the first three visits. If this were taken as an indication to withhold drug treatment, 3 years later one-quarter of them (4% of all subjects) would be found to be hypertensive or to have experienced a trial end-point, and thus inappropriately untreated, while the other 12% would have pressures below 95 mm Hg and have had no trial end-point.
To the Editor.—
JAMA recently published comments on the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) Study, together with a response from the authors.1 I have some additional remarks.Although the Heart Attack Primary Prevention in Hypertension (HAPPHY) and MAPHY trials are judged as different by the Steering Committee of the HAPPHY trial, the MAPHY trial cannot be interpreted independently of the HAPPHY trial findings because all patients in the MAPHY Study are in the HAPPHY trial. Therefore, the meta-analysis presented by Staessen et al cannot be used for comparison of the MAPHY Study with previous trials.1 The only valid way the comparison could be done would be to make a meta-analysis of the Medical Research Council trial and the International Prospective Primary Prevention Study in Hypertension and the atenolol part of the HAPPHY trial.The Steering Committee of the HAPPHY trial, therefore, should publish the results in the
Background In patients with heart failure, beta-blochade has improved morbidity and left-ventricular function, but the impact on survival is uncertain. We investigated the efficacy of bisoprolol, a beta(1) selective adrenoceptor blocker in decreasing all-cause mortality in chronic heart failure. Methods In a multicentre double-blind randomised placebo-controlled trial in Europe, we enrolled 2647 symptomatic patients in New York Heart Association class III or IV, with left-ventricular ejection fraction of 35% or less receiving standard therapy with diuretics and inhibitors of angiotensin-converting enzyme. We randomly assigned patients bisoprolol 1.25 mg (n=1327) or placebo (n=1320) daily, the drug being progressively increased to a maximum of 10 mg per day. Patients were followed up for a mean of 1.3 years. Analysis was by intention to treat. Findings CIBIS-II was stopped early, after the second interim analysis, because bisoprolol showed a significant mortality benefit. All-cause mortality was significantly lower with bisoprolol than on placebo (156 [11.8%] vs 228 [17.3%] deaths with a hazard ratio of 0.66 (95% CI 0.54-0.81, p<0.0001). There were significantly fewer sudden deaths among patients on bisoprolol than in those on placebo (48 [3.6%] vs 83 [6.3%] deaths), with a hazard ratio of 0.56 (0.39-0.80, p=0.0011). Treatment effects were independent of the severity or cause of heart failure. Interpretation beta-blocker therapy had benefits for survival in stable heart-failure patients. Results should not, however, be extrapolated to patients with severe class IV symptoms and recent instability because safety and efficacy has not been established in these patients.
The benefits of reducing blood pressure on the risks of major cardiovascular disease are well established, but uncertainty remains about the comparative effects of different blood-pressure-lowering regimens. We aimed to estimate effects of strategies based on different drug classes (angiotensin-converting-enzyme [ACE] inhibitors, calcium antagonists, angiotensin-receptor blockers [ARBs], and diuretics or β blockers) or those targeting different blood pressure goals, on the risks of major cardiovascular events and death.
Currentmethods for assessing vasomotor endothelial function are impractical for use in large studies. We tested the hypothesis that pulse-wave analysis (PWA) combined with provocative pharmacological testing might provide an alternative method. Radial artery waveforms were recorded and augmentation index (AIx) was calculated from derived aortic waveforms. Thirteen subjects received sublingual nitroglycerin (NTG), inhaled albuterol, or placebo. Twelve subjects received NTG, albuterol, and placebo separately during an infusion of N G-monomethyl-l-arginine (LNMMA) or norepinephrine. Twenty-seven hypercholesterolemic subjects and 27 controls received NTG followed by albuterol. Endothelial function was assessed by PWA and forearm blood flow in 27 subjects. Albuterol and NTG both significantly and repeatably reduced AIx ( P <0.001). Only the response to albuterol was inhibited by LNMMA (−9.8±5.5% vs −4.7±2.7%; P =0.02). Baseline AIx was higher in the hypercholesterolemic subjects, who exhibited a reduced response to albuterol ( P =0.02) but not to NTG when compared with matched controls. The responses to albuterol and acetylcholine were correlated ( r =0.5, P =0.02). Consistent with an endothelium-dependent effect, the response to albuterol was substantially inhibited by LNMMA. Importantly, the response to albuterol was reduced in subjects with hypercholesterolemia and was correlated to that of intra-arterial acetylcholine. This methodology provides a simple, repeatable, noninvasive means of assessing endothelial function in vivo.
Angiotension converting enzyme (ACE) inhibitors and β-blockers have been reported to possess disparate effects on insulin
sensitivity. The aim of this study was to study the effects of the selective β-1 blocker bisoprolol and of the ACE inhibitor
captopril on cellular insulin action in hypertensive individuals. After washout, 12 mild to moderate essential hypertensives
were randomized in a double-blind manner to 5 mg bisoprolol daily or 25 mg captopril twice daily for 8 weeks. Erythrocyte
insulin binding and insulin-stimulated tyrosine kinase (TK) activity were measured before and after therapy. Both agents decreased
diastolic blood pressure significantly (bisoprolol 96.5 ± 0.9 to 87.8 ± 3.1 mm Hg; captopril 96.5 ± 0.9 to 91.5 ± 1.8 mm Hg;
P < .05). Fasting plasma glucose, insulin, and insulin/glucose indices remained unchanged after both therapies, as did lipid
profiles. Maximal insulin-stimulated TK activity, assessed by phosphorylation of the exogenous substrate poly-Glu80Tyr20, was significantly higher (P < .05) after bisoprolol treatment, but not after captopril treatment, when compared to placebo (bisoprolol 8.5 ± 1.8; captopril
7.3 ± 1.5; placebo: 6.4 ± 1.3 pmol 32P-ATP/fmol bound insulin). However, captopril, but not bisoprolol, increased the sensitivity of the receptor TK activity,
as measured by the half-maximal activity concentration (ED50). Specific insulin binding was not affected by these two agents. Thus, both captopril and bisoprolol may have favorable but
different effects on TK activity and insulin action at the cellular level. Am J Hypertens 1997;10:1326–1334 © 1997 American
Journal of Hypertension, Ltd.
Both [beta]-blockers and angiotensin-converting enzyme (ACE) inhibitors have been shown to cause left ventricular hypertrophy regression in hypertensive patients. So far, no study allowed a true comparison of these drugs in this regard. Therefore, 56 hypertensive patients (38 newly recognized and 18 without any antihypertensive drugs for more than 2 months, mean of 9.5 +/- 14 months) were randomized to enalapril (En, n = 30) or a [beta]-blocker, bisoprolol (Bi, n = 26), once daily and underwent before and after 2 and 6 months on treatment (a) office and 24-h ambulatory monitoring of BP, (b) M-mode echo assessment of left ventricular mass (LVM) index and fractional shortening (FS), and (c) Doppler evaluation of left ventricular filling. All recordings were read blindly by two observers. The intraobserver coefficient of variation of LVM was 9%. After 6 months, office BP(146 +/- 18/90 +/- 10 vs. 170 +/- 14/104 +/- 8 mm Hg) and 24-h-BP (120 +/- 7/77 +/- 9 vs. 138 +/- 15/90 +/- 9 mm Hg) were similarly reduced with both drugs. The LVM index was significantly reduced (p < 0.001) (Bi, 11%; En. 7%) and FS was unchanged. The early to late diastolic left ventricular flow ratio (K/A) was increased with bisoprolol (1.06 +/- 0.29 vs. 0.85 +/- 0.17, p < 0.0001) but not with enalapril (0.95 +/- 0.24 vs. 0.88 +/- 0.34), but this was mainly due to heart rate reduction with bisoprolol. We found no correlation between the reductions in 24-h BP and in LVM index. Bisoprolol and enalapril were similarly effective in lowering blood pressure (BP) in the office and during 24-h monitoring and in reducing the left ventricular mass index in hypertensive patients.
Objective: The aim of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation study was to compare the long-term effect of the commonly used inexpensive medication with a low-dose diuretic (hydrochlorothiazide), alone or in combination with a β-adrenoceptor (atenolol), with that of more modern but also more expensive antihypertensive treatment with an angiotensin-II-receptor blocker (candesartan), alone or in combination with a calcium antagonist (felodipine), and to do so in newly diagnosed patients with primary hypertension. The objectives included comparisons of the effects on the glucose metabolism, lipoprotein metabolism, electrolytes, blood pressure, and subjective symptoms. Design: A 1-year, prospective randomized, double-blind, controlled trial. Subjects: In an investigator-initiated study, we included 392 patients (mean age 55 years, 48% men); 370 patients (94%) had never been treated with antihypertensive drugs before the study. No patient was lost to follow-up. Results: Both treatment regimens lowered blood pressure well (23/13 mmHg in the hydrochlorothiazide group and 21/13 mmHg in the candesartan group), with a majority of patients needing two drugs. Fasting levels of both serum insulin and plasma glucose increased in the hydrochlorothiazide group in contrast to unaffected levels in the candesartan group. Diabetes mellitus was diagnosed in nine patients during follow-up, in eight patients in the hydrochlorothiazide group (4.1%) and in one patient (0.5%) in the candesartan group (P = 0.030). Triglycerides increased and high-density lipoprotein-cholesterol decreased more in the hydrochlorothiazide group than in the candesartan group. Both the low-density lipoprotein/high-density lipoprotein and the apolipoprotein B/apolipoprotein A-I ratios increased in the hydrochlorothiazide group. At 12 months, 18 patients in the hydrochlorothiazide group versus five in the candesartan group had a ‘metabolic syndrome', as defined by the World Health Organization (P = 0.007) despite 1 year of active blood pressure-lowering therapy. There were less (P = 0.020) adverse events in the candesartan group, but no major differences in the subjective symptoms assessment profile. One subject in each group had a myocardial infarction. Conclusion: Antihypertensive treatment with a diuretic, if needed combined with a β-adrenoceptor blocker, was associated with an aggravated metabolic profile; this was not so for patients treated with an angiotensin-II-receptor blocker, if needed combined with a calcium antagonist. An antihypertensive treatment strategy that costs more in the short run but has no metabolic adverse effects may have a health economic impact in the long term.
Obesity has become pandemic in the United States. Currently, 2 in 3
US adults are classified as overweight or obese, compared with fewer than
1 in 4 in the early 1960s.1,2 Although
still viewed more as a cosmetic rather than a health problem by the general
public, excess weight is a major risk factor for premature mortality, cardiovascular
disease, type 2 diabetes mellitus, osteoarthritis, certain cancers, and other
medical conditions.3 Obesity accounts for more
than 280 000 deaths annually in the United States and will soon overtake
smoking as the primary preventable cause of death if current trends continue.4 Indeed, obesity is already associated with greater
morbidity and poorer health-related quality of life than smoking, problem
drinking, or poverty.5 Despite this, excess
weight has not received the same attention from clinicians and policymakers
as have other threats to health such as tobacco use, hypertension, or hypercholesterolemia.
Given these circumstances, it is not surprising that obesity rates continue
to climb, even as significant reductions in other risk factors have been achieved.6
Although vascular compliance, ΔV/ΔP, is abnormal in essential hypertension and can be improved by antihypertensive drug therapy, it is not clear whether drug-induced changes in compliance are attributable solely to lower achieved blood pressure (BP), and thus equally likely with different drugs possessing similar antihypertensive efficacy. Therefore, we used computerized arterial pulse waveform analysis (CAPWA) to measure capacitive (C1) and oscillatory (C2) components of arterial compliance in essential hypertensive subjects (n = 39) before, and 1 and 3 months after achieving normotensive BP values with administration of either dihydropyridine calcium channel antagonists (CaBl, n = 11), converting enzyme inhibitors (CEI, n = 9), angiotensin receptor blockers (ARB, n = 9), or β-blockers (BBl, n = 10).
Despite equivalent effects on BP (CaBl: −19 ± 4/−15 ± 2 mm Hg; CEI: −12 ± 3/−13 ± 2 mm Hg; ARB: −10 ± 3/−12 ± 2 mm Hg; and BBl: −14 ± 3/−12 ± 2 mm Hg; P < .005 for each drug v pretreatment), CaBl, CEI, and ARB significantly increased arterial compliance (CaBl: %ΔC1 = 30.0 ± 5.8, %Δ C2 = 43.7 ± 23.3; CEI: %ΔC1 = 32.7 ± 5.4, %ΔC2 = 26.7 ± 7.1; ARB: %ΔC1 = 36.3 ± 11.8, %ΔC2 = 43.6 ± 23.1; P < .01 for CaBl, CEI, and ARB v pretreatment), but BBl did not (%ΔC1 = −3.9 ± 7.6, %ΔC2 = −7.0 ± 11.5, P = not significant v pretreatment, sig = 0.01 v other drugs). We conclude that for an equivalent effect on BP, arterial compliance improves after therapy with some, but not all antihypertensive drugs. We hypothesize that a greater clinical benefit may result from the preferential use of drugs that concomitantly improve arterial compliance. Am J Hypertens 2002;15:1096–1100 © 2002 American Journal of Hypertension, Ltd.
516 patients with New York Heart Association class III and IV heart failure despite treatment with diuretics and angiotensin converting enzyme inhibitors were randomised in a double-blind between-group comparison to xamoterol 200 mg (352) or placebo (164) twice daily for 13 weeks. There was no difference between the treatments in loss of clinical signs. Visual analogue scale and Likert scores indicated that breathlessness was less severe with xamoterol, but there was no difference in exercise duration or total work done. Xamoterol reduced maximum exercise heart rate and systolic blood pressure, did not affect the number of ventricular premature beats after exercise, showed no arrhythmogenic activity, and had variable (agonist and antagonist) effects on 24 h heart rate. On intention-to-treat analysis 32 (9.1%) patients in the xamoterol group and 6 (3.7%) patients in the placebo group died within 100 days of randomisation (p = 0.02).
CONTEXT β-Blockade therapy has recently been shown to convey a survival benefit in preoperative noncardiac vascular surgical settings. The effect of preoperative β-blocker therapy on coronary artery bypass graft surgery (CABG) outcomes has not been assessed. OBJECTIVES To examine patterns of use of preoperative β-blockers in patients undergoing isolated CABG and to determine whether use of β-blockers is associated with lower operative mortality and morbidity. DESIGN, SETTING, AND PATIENTS Observational study using the Society of Thoracic Surgeons National Adult Cardiac Surgery Database (NCD) to assess β-blocker use and outcomes among 629 877 patients undergoing isolated CABG between 1996 and 1999 at 497 US and Canadian sites. MAIN OUTCOME MEASURE Influence of β-blockers on operative mortality, examined using both direct risk adjustment and a matched-pairs analysis based on propensity for preoperative β-blocker therapy. RESULTS From 1996 to 1999, overall use of preoperative β-blockers increased from 50% to 60% in the NCD (P<.001 for time trend). Major predictors of use included recent myocardial infarction; hypertension; worse angina; younger age; better left ventricular systolic function; and absence of congestive heart failure, chronic lung disease, and diabetes. Patients who received β-blockers had lower mortality than those who did not (unadjusted 30-day mortality, 2.8% vs 3.4%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.78-0.82). Preoperative β-blocker use remained associated with slightly lower mortality after adjusting for patient risk and center effects using both risk adjustment (OR, 0.94; 95% CI, 0.91-0.97) and treatment propensity matching (OR, 0.97; 95% CI, 0.93-1.00). Procedural complications also tended to be lower among treated patients. This treatment advantage was seen among the majority of patient subgroups, including women; elderly persons; and those with chronic lung disease, diabetes, or moderately depressed ventricular function. Among patients with a left ventricular ejection fraction of less than 30%, however, preoperative β-blocker therapy was associated with a trend toward a higher mortality rate (OR, 1.13; 95% CI, 0.96-1.33; P = .23). CONCLUSIONS In this large North American observational analysis, preoperative β-blocker therapy was associated with a small but consistent survival benefit for patients undergoing CABG, except among patients with a left ventricular ejection fraction of less than 30%. This analysis further suggests that preoperative β-blocker therapy may be a useful process measure for CABG quality improvement assessment.