Nebivolol versus placebo in patients undergoing anthracyclines (CONTROL Trial): rationale and study design.

AIMS: Anthracyclines are the chemotherapeutic agents most frequently associated with cardiotoxicity, while remaining widely used. Different neurohormonal blockers have been tested as a primary prevention strategy to prevent or attenuate the onset of cardiotoxicity, with mixed results. However, prior studies were often limited by a nonblinded design and an assessment of cardiac function based only on echocardiographic imaging. Moreover, on the basis of an improved mechanistic understanding of anthracycline cardiotoxicity mechanisms, new therapeutic strategies have been proposed. Among cardioprotective drugs, nebivolol might be able to prevent the cardiotoxic effects of anthracyclines, through its protective properties towards the myocardium, endothelium, and cardiac mitochondria. This study aims to evaluate the cardioprotective effects of the beta blocker nebivolol in a prospective, placebo-controlled, superiority randomized trial in patients with breast cancer or diffuse large B cell lymphoma (DLBCL) who have a normal cardiac function and will receive anthracyclines as part of their first-line chemotherapy programme. METHODS: The CONTROL trial is a randomized, placebo-controlled, double-blinded, superiority trial. Patients with breast cancer or a DLBCL, with a normal cardiac function as assessed by echocardiography, scheduled for treatment with anthracyclines as part of their first-line chemotherapy programme will be randomized 1 : 1 to nebivolol 5 mg once daily (o.d.) or placebo. Patients will be examined with cardiological assessment, echocardiography and cardiac biomarkers at baseline, 1 month, 6 months and 12 months. A cardiac magnetic resonance (CMR) assessment will be performed at baseline and at 12 months. The primary end point is defined as left ventricular ejection fraction reduction assessed by CMR at 12 months of follow-up. CONCLUSION: The CONTROL trial is designed to provide evidence to assess the cardioprotective role of nebivolol in patients undergoing chemotherapy with anthracyclines. CLINICAL TRIAL REGISTRATION: The study is registered in the EudraCT registry (number: 2017-004618-24) and in the ClinicalTrials.gov registry (identifier: NCT05728632).

Effects of Major Antihypertensive Drug Classes on Erectile Function: a Network Meta-analysis.

PURPOSE: To determine the effect of major antihypertensive classes on erectile function (EF) in patients with or at high risk of cardiovascular disease. METHODS: We performed a systematic review and frequentist network meta-analysis of randomized controlled trials assessing the effect of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, calcium channel blockers, and thiazide diuretics on EF compared to each other and to placebo (PROSPERO: CRD42020189529). Similarly, we performed a network meta-analysis to explore the effect of different ß-blockers on erectile function (nebivolol, other vasodilating and non-vasodilating ß-blockers, placebo). Records were identified through search of PubMed, Cochrane Library, and Scopus databases and sources of grey literature until September 2020. RESULTS: We included 25 studies (7784 patients) in the qualitative and 16 studies in the quantitative synthesis. The risk of bias was concerning or high in the majority of studies, and inconsistency was also high. No significant differences in EF were demonstrated in the pairwise comparisons between major antihypertensive classes. Similarly, when placebo was set as the reference treatment group, no treatment strategy yielded significant effects on EF. In the ß-blockers analysis, nebivolol contributed a beneficial effect on EF only when compared to non-vasodilatory ß-blockers (OR 2.92, 95%CI 1.3-6.5) and not when compared to placebo (OR 2.87, 95%CI 0.75-11.04) or to other vasodilatory ß-blockers (OR 2.15, 95%CI 0.6-7.77). CONCLUSION: All antihypertensive medication classes seem to exert neutral or insignificant effects on EF. Further high-quality studies are needed to better explore the effects of antihypertensive medication on EF.

Therapeutic Properties of Highly Selective ß-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease.

Bisoprolol and nebivolol are highly selective ß1-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" ß-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.

Comprehensive Comparative Effectiveness and Safety of First-Line ß-Blocker Monotherapy in Hypertensive Patients: A Large-Scale Multicenter Observational Study.

[Figure: see text].

Effects of nebivolol versus other antihypertensive drugs on the endothelial dysfunction in patients with essential hypertension.

We aim to determine whether nebivolol has a better effect on endothelial dysfunction compared with other ß-blockers or other classes of antihypertensive drugs. Searches of the PubMed, Embase etc. were performed to analyze all the randomized controlled trials using nebivolol to treat essential hypertension. The primary end points included a measurement of peripheral endothelial function by brachial flow mediated vasodilatation (FMD) or forearm blood flow (FBF). A random-effect model was used to perform the meta-analysis when the studies showed significant heterogeneity, otherwise a descriptive analysis was conducted. Ten studies (689 patients) were included in qualitative analysis, four of which were included in quantitative synthesis. Meta-analysis showed that the changed FMD value before and after treatment with nebivolol was not statistically different from those treated with other ß-blockers [mean difference = 1.12, 95% confidence interval (CI): -0.56, 2.81, P=0.19]. Descriptive analysis indicated that nebivolol did not have a better endothelium-protective effect than other classes of antihypertensive drugs including olmesartan and perindopril. Nebivolol is not a unique endothelial function-protective agent distinguished from other ß-blockers or other classes of antihypertensive drugs. Reversal of endothelial dysfunction is a key point in the prevention and therapy of essential hypertension.

A Critical Review of Nebivolol and its Fixed-Dose Combinations in the Treatment of Hypertension.

ß-Adrenergic receptor blockers (ß-blockers) are well-known useful and cost-effective drugs for managing hypertensive patients with coronary heart disease, stroke, and heart failure. However, it is often difficult to use ß-blockers for patients with asthma or chronic obstructive pulmonary disease (COPD). Moreover, most ß-blockers negatively influence glucose or lipid metabolism. Nebivolol is a third-generation lipophilic ß-1 receptor-selective blocker with nitric oxide-mediated vasodilatory effects, metabolically neutral and usually well tolerated by patients with asthma or COPD. Nebivolol has significant effects of reduction in central blood pressure and improvements in endothelial dysfunction and arterial stiffness. To summarize the merits and demerits of nebivolol in different clinical situations, we conducted a review using the word 'nebivolol' on Pubmed and Embase, limiting the search to hypertension, clinical trials, and meta-analyses. This review summarizes the clinical studies on nebivolol itself and on the combination of nebivolol with other antihypertensive drugs, such as hydrochlorothiazide, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and amlodipine. Most studies showed the safety and well-tolerated profile of nebivolol and the combination of nebivolol with other antihypertensive drugs, which suggests that new fixed combinations of nebivolol with other antihypertensive drugs would be useful for patients who are unable to tolerate traditional ß-blockers.

Insights on ß-blockers for the treatment of hypertension: A survey of health care practitioners.

A quantitative survey was completed by 103 primary care physicians (PCPs) and 59 cardiologists who regularly prescribed ß-blockers to assess knowledge and use of this heterogeneous drug class for hypertension. More cardiologists than PCPs chose ß-blockers as initial antihypertensive therapy (30% vs 17%, P < 0.01). Metoprolol and carvedilol were the most commonly prescribed ß-blockers. Cardiologists rated "impact on energy" and "arterial vasodilation" as more important than PCPs (P < 0.05/<0.01, respectively). Awareness of vasodilation was greater for carvedilol (52%) than nebivolol (31%). Association between ß-blockers and clinical variables included nebivolol with ß1 -selectivity, nebivolol and carvedilol with vasodilation and efficacy in older patients and African Americans, metoprolol with heart rate reduction, and atenolol and metoprolol with weight gain and hyperglycemia. Physicians preferred prescribing ß-blockers with lower risk of incident diabetes. Clinical practice guidelines influenced physician prescribing more than formularies or performance metrics. This survey captures physicians' perceptions/use of various ß-blockers and clinically relevant knowledge gaps.

A retrospective study evaluating the tolerability and effectiveness of adjunctive antihypertensive drugs in patients with inadequate response to initial treatment.

Real-world tolerability and effectiveness of nebivolol as first add-on therapy were compared with hydrochlorothiazide, metoprolol, and amlodipine. Medical records of hypertensive adults initiating nebivolol, hydrochlorothiazide, metoprolol, or amlodipine as first add-on therapy between December 16, 2010 and July 21, 2011 were retrospectively abstracted (N = 1600; 400/treatment). Outcomes included medication-related side-effect rates and blood pressure (BP) reduction and control. Compared with nebivolol, metoprolol and amlodipine had significantly higher side-effect rates (incidence rate ratio [95% CI]: 1.82 [1.14-2.92] and 2.67 [1.69-4.21]), respectively); the hydrochlorothiazide-nebivolol rate ratio was not significant (1.61 [0.95-2.71]). All treatments reduced BP at 2 months. Metoprolol, amlodipine, and hydrochlorothiazide were associated with significantly lower odds of achieving 2-month BP control than nebivolol (odds ratios [95% CI]: 0.34 [0.23-0.51], 0.51 [0.35-0.75] and 0.66 [0.44-0.99], respectively). In a real-world setting, nebivolol as first add-on therapy was associated with fewer side effects than metoprolol or amlodipine and with a higher BP control rate than hydrochlorothiazide, metoprolol, or amlodipine.

Additivity of nebivolol/valsartan single-pill combinations versus other single-pill combinations for hypertension.

The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory ß1 -selective antagonist/ß3 -agonist, and valsartan (80 mg), a renin-angiotensin-aldosterone system inhibitor, is the only Food and Drug Administration-approved ß-blocker/renin-angiotensin-aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration-approved non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo-adjusted SPC blood pressure (BP) reduction to the placebo-adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735-0.866; systolic BP range: 0.717-0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs were comparable.

Lichenoid type cutaneous hyperpigmentation induced by nebivolol.

Cutaneous hyperpigmentation is a common and well-defined side effect of many drugs, such as non-steroidal anti-inflammatory drugs, beta-blockers, and tetracyclines, but to the best of our knowledge there is no case of skin discoloration related to nebivolol in the literature. Presently described is lichenoid type cutaneous hyperpigmentation in a 46-year-old female patient. Hyperpigmentation emerged 3 months after initiating use of nebivolol and resolved after cessation of drug use. It was concluded that effect emerged as result of therapeutic doses of nebivolol.

Role of nebivolol in the control and management of central aortic blood pressure in hypertensive patients.

Measurement of blood pressure (BP) using a brachial cuff sphygmomanometer is universally accepted for the diagnosis of hypertension and prediction of cardiovascular diseases. However, brachial systolic BP does not represent actual systolic BP in the central arteries which encounter cardiac load directly. Due to wave amplification from central to peripheral arteries, a significant difference exists between the two. Central BP measurements also account for arterial stiffness, vessel branching and vascular mechanics, unlike brachial BP. Emerging data suggests that hypertension can be diagnosed more accurately by central pressure indices as compared to brachial BP. Various non-invasive techniques are now available to measure central BP indices owing to recent technological advances. Recently, it has been reported that different classes of anti-hypertensive drugs display differential effects on brachial and central BPs. Nebivolol is a cardio-selective beta-blocker which targets central systolic BP and reduces it significantly along with brachial BP. In this article, we will review the current literature to evaluate the role of central BP to diagnose hypertension in detail. We will also assess the clinical evidence to evaluate the role of nebivolol in the management of elevated central systolic BP. Central BP indices offer better estimation of BP in central arteries and should be considered in routine clinical practice. Nebivolol has shown significant reduction in aortic pressure and wave reflection and improvements in endothelial dysfunction and arterial stiffness in hypertensive patients.

Nebivolol/valsartan: Fixed-dose combination for treatment of hypertension.

Clinical trials demonstrated that a fixed-dose combination (FDC) of the beta-blocker nebivolol (5 mg) and the angiotensin II antagonist valsartan (80 mg) produced a significant reduction of both diastolic and systolic blood pressure in patients with hypertension. Both nebivolol and valsartan contributed to this effect, partial additivity of 86.6% and 82.2% being observed for diastolic and systolic blood pressure, respectively. These values are very similar to the additivity ratios of other recently approved FDCs for hypertension. Use of the FDC nebivolol 5 mg/valsartan 80 mg formulation was associated with a low incidence of treatment-related adverse effects and of serious adverse effects. There was no evidence of adverse effects due to beta2-adrenoceptor blockade. The FDC (Byvalson) was approved and launched in 2016 in the U.S. for the treatment of hypertension.

The Comparison of the Effects of Nebivolol and Metoprolol on Erectile Dysfunction in the Cases with Coronary Artery Bypass Surgery.

PURPOSE: Beta-blocker use is common in the cases with coronary artery bypass surgery. According to the literature, beta-blockers have positive effects but may cause erectile dysfunction (ED). The most commonly used beta-blockers in ischemic cardiac disease are nebivolol and metoprolol. In our clinic, we aimed to compare the effects of nebivolol and metoprolol succinate on ED in the sexually active cases with coronary artery bypass surgery. METHODS: In our clinic, a total of 119 patients with coronary artery bypass surgery were included in the study. International Index of Erectile Function (IIEF-5) Test was used to evaluate whether the patients had ED and to grade the cases. RESULTS: No significant difference was found in terms of anti-ischemic efficacy between metoprolol succinate and nebivolol in the postoperative period; however, the incidence of any grade ED was %85.96 in Group 1, %83.87 in Group 2. This difference was considered as statistically significant (p = 0.036). CONCLUSION: Beta-blocker use increases the risk of ED in cases with ischemic cardiac disease. We suggest that the complaints of ED could be less frequent with nebivolol use in sexually active cases with ischemic cardiac disease.

Comparative effects of nebivolol and carvedilol on left ventricular diastolic function in older heart failure patients with preserved ejection fraction: study protocol for a randomized controlled trial.

BACKGROUND: Heart failure (HF) is a common and disabling condition in older people. Randomized clinical trials and meta-analyses have clearly demonstrated that the long-term use of ß-Blockers improves the outcome of patients with HF. However, limited data are available on the treatment of older HF patients with preserved ejection fraction (EF). No study has specifically compared the relative effectiveness of carvedilol and nebivolol in treating HF in older patients with preserved EF. METHOD/DESIGN: This trial is a prospective, randomized, open-label, single-centre, active controlled study designed to investigate the effects of nebivolol and carvedilol on diastolic function of the left ventricle (LV) in older HF patients with preserved EF. We will test the hypothesis that nebivolol improves LV diastolic function to a greater extent than carvedilol in patients over 70 years of age. The study population includes 62 older patients newly diagnosed with HF. Patients will be included in the study if they have a LVEF ≥40 %, New York Heart Association (NYHA) functional classes I, II or III status, and have been clinically stable without hospital admission for HF in the preceding 3 months. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive a loading and maintenance dose of either nebivolol or carvedilol. Echocardiographic evaluations will be performed at baseline, 6, and 12 months after therapy. Clinical assessment and laboratory tests are to be performed at fixed times. DISCUSSION: This trial is a single-center study that aims to evaluate the impact of nebivolol on LV diastolic function. The results of the study will provide information about the optimal choice of a ß-Blocker in the management of patients after diagnosis of HF with preserved EF. The results will be available by 2017. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02619526 , registered on 25 November 2015.

Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans.

Use of ß-adrenergic receptor (AR) blocker is associated with increased risk of fatigue and exercise intolerance. Nebivolol is a newer generation ß-blocker, which is thought to avoid this side effect via its vasodilating property. However, the effects of nebivolol on skeletal muscle perfusion during exercise have not been determined in hypertensive patients. Accordingly, we performed contrast-enhanced ultrasound perfusion imaging of the forearm muscles in 25 untreated stage I hypertensive patients at rest and during handgrip exercise at baseline or after 12 wk of treatment with nebivolol (5-20 mg/day) or metoprolol succinate (100-300 mg/day), with a subsequent double crossover for 12 wk. Metoprolol and nebivolol each induced a reduction in the resting blood pressure and heart rate (130.9 ± 2.6/81.7 ± 1.8 vs. 131.6 ± 2.7/80.8 ± 1.5 mmHg and 63 ± 2 vs. 64 ± 2 beats/min) compared with baseline (142.1 ± 2.0/88.7 ± 1.4 mmHg and 75 ± 2 beats/min, respectively, both P < 0.01). Metoprolol significantly attenuated the increase in microvascular blood volume (MBV) during handgrip at 12 and 20 repetitions/min by 50% compared with baseline (mixed-model P < 0.05), which was not observed with nebivolol. Neither metoprolol nor nebivolol affected microvascular flow velocity (MFV). Similarly, metoprolol and nebivolol had no effect on the increase in the conduit brachial artery flow as determined by duplex Doppler ultrasound. Thus our study demonstrated a first direct evidence for metoprolol-induced impairment in the recruitment of microvascular units during exercise in hypertensive humans, which was avoided by nebivolol. This selective reduction in MBV without alteration in MFV by metoprolol suggested impaired vasodilation at the precapillary arteriolar level.

Nebivolol Induced Hyperkalemia: Case Report

In this article, we document a conclusive case of nebivolol-induced hyperkalemia for the first time in the known medical literature. Hyperkalemia is associated with serious conditions such as cardiac arrhythmias and sudden cardiac death. Nebivolol was not known to cause hyperkalemia, and this event is not listed in its summary of product characteristics (SmPC). For older beta blockers, hyperkalemia is recognized as a rare adverse event linked to cytochrome P450 2D6 (CYP2D6) polymorphism and poor drug degradation. Our patient, a 47-year-old woman taking nebivolol for hypertension developed persistent hyperkalemia, with serum potassium levels up to 6.4 mmol/L. After extensive diagnostic evaluation and exclusion of other known conditions leading to hyperkalemia, its cause remained occult. Since hyperkalemia coincided with increased doses of nebivolol, dose reduction and discontinuation were attempted, resulting in normalized serum potassium. Poor drug metabolism could not explain this adverse effect, since pharmacogenetic testing showed no relevant aberrations. In conclusion, hyperkalemia is a harmful adverse event with possible lethal outcome, and it may be caused by nebivolol. Therefore, medical professionals have to be aware of this side effect and hyperkalemia should be listed as an adverse event in nebivolol SmPC.

A Review of Nebivolol Pharmacology and Clinical Evidence.

Nebivolol is a highly selective ß1-adrenergic receptor antagonist with a pharmacologic profile that differs from those of other drugs in its class. In addition to cardioselectivity mediated via ß1 receptor blockade, nebivolol induces nitric oxide-mediated vasodilation by stimulating endothelial nitric oxide synthase via ß3 agonism. This vasodilatory mechanism is distinct from those of other vasodilatory ß-blockers (carvedilol, labetalol), which are mediated via α-adrenergic receptor blockade. Nebivolol is approved for the treatment of hypertension in the US, and for hypertension and heart failure in Europe. While ß-blockers are not recommended within the current US guidelines as first-line therapy for treatment of essential hypertension, nebivolol has shown comparable efficacy to currently recommended therapies in lowering peripheral blood pressure in adults with hypertension with a very low rate of side effects. Nebivolol also has beneficial effects on central blood pressure compared with other ß-blockers. Clinical data also suggest that nebivolol may be useful in patients who have experienced erectile dysfunction while on other ß-blockers. Here we review the pharmacological profile of nebivolol, the clinical evidence supporting its use in hypertension as monotherapy, add-on, and combination therapy, and the data demonstrating its positive effects on heart failure and endothelial dysfunction.