Benefits of 3rd Generation Beta-blockers in Antihypertensive Therapy

Prof. Rafael R. Castillo
Dr. Hyo Seung Ahn
20 Aug 2019
Benefits of 3rd Generation Beta-blockers in Antihypertensive Therapy
Major trials have demonstrated the benefits of beta-blockers in the treatment of hypertension.1 At a recent symposium held during the Asian Pacific Society of Cardiology 2019 Congress in Manila, Philippines, experts discussed the latest guidelines on hypertension treatment, with a focus on the role of the 3rd generation beta-blocker, nebivolol. The symposium was chaired by Dr Dante D. Morales, Clinical Associate Professor at the University of the Philippines College of Medicine, and featured renowned cardiologists Prof Rafael R. Castillo and Dr Hyo Seung Ahn.

Role of Beta blockers
In a controversial move, the American College of Cardiology (ACC), together with the American Heart Association (AHA) and 9 other American societies, issued guidelines in 2017 that redefined hypertension (HTN) to equal or above 130/80 mm Hg, thereby lowering the target blood pressure (BP) goals.2,3 Similarly, the 2018 European Society of Cardiology/ European Society of Hypertension (ESC/ESH)  guidelines recommend that BP targets should be <140/90 mm Hg in all patients, and further lowered to 130/80 mm Hg or lower in patients aged <65 years, if tolerated.4

Both guidelines emphasize therapeutic lifestyle changes as the foundation of HTN management. These include weight loss for overweight or obese patients, adherence to a heart-healthy diet, sodium reduction, potassium supplementation, smoking cessation, regular physical activity, and reduced alcohol consumption. Effective lifestyle changes may be enough to delay or prevent the need for drug therapy, particularly in low-risk hypertensive patients with grade 1 HTN, though the vast majority of patients will require drug therapy in addition to lifestyle modification to achieve optimal BP control.

For many decades, the recommended treatment strategy for HTN has been the stepped-care approach, wherein drug therapy is initiated with a single agent, followed by sequential titration and addition of other agents.2 However, recent guidelines recommend initiation of antihypertensive drug therapy with two agents from different pharmacological classes.2,4 This strategy can help physicians overcome the clinical inertia of titrating and adding agents to achieve BP targets, as multiple agents are often required.

Preferred first-line agents include thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs), while the use of beta-blockers is generally reserved for patients with specific cardiovascular comorbidities or compelling indications.2 The ESC/ESH states that beta-blockers may be considered at any treatment step when there is a specific indication for their use, such as heart failure, angina, post-myocardial infarction, atrial fibrillation, or in women planning pregnancy or of child-bearing potential.4

In the past, beta-blockers have been relegated from first-line antihypertensive agents to secondary agents, due to clinical concerns about its efficacy to reduce BP compared to other drug classes, and less efficacy to reduce  CV events compared to other drugs. However, meta-analyses do not support this. A robust meta-analysis of 354 randomized double-blind, placebo-controlled trials of thiazides, beta-blockers, ACE inhibitors, ARBs, and CCBs showed that all five categories of drug produced similar reductions in BP.5 Moreover, a large meta-analysis of randomized trials conducted by the Blood Pressure Lowering Treatment Trialists’ Collaboration showed no clear differences between the effects of the drug classes on major cardiovascular events.6

Another criticism was the lack of evidence of cardiovascular protection in placebo-controlled trials, but this finding was largely based on unfavourable clinical data from trials involving first- and second-generation beta-blockers7, while unfairly implicating third-generation beta-blockers. Notably, beta-blockers are not a homogeneous class (Figure 1)1, with differing pharmacokinetic and pharmacodynamic profiles. Compared with classical beta-blockers, vasodilating beta-blockers have a considerably better metabolic, haemodynamic, and side effect profile. Among currently available beta-blockers, nebivolol has the highest beta1-selectivity.8 Whereas carvedilol exerts vasodilatory effects through alpha1-receptor inhibition, nebivolol enhances vasodilation and blood flow through stimulating nitric oxide (NO) release, thereby improving endothelial function.7

Benefit Fig01
The 2009 ESH reappraisal and 2013 ESH/ESC guidelines recognize that beta-blockers are indeed suitable for initial therapy in HTN and that highly beta1-selective blockers or those with vasodilatory effects may be preferred as first-line antihypertensive agents.9,10 The 2018 ESC/ESH guidelines noted that the use of vasodilating beta-blockers has increased.4 In particular, studies on nebivolol have shown improvement of central BP,11 aortic stiffness, and endothelial dysfunction, while having no adverse effects on metabolic profile,12 and fewer side effects than classical beta-blockers, including less adverse effects on sexual function.4,13

In this era of personalized medicine, it is important to consider patient-specific factors such as age, concurrent medications, drug adherence, drug-interactions, comorbidities and costs when selecting antihypertensive agents. Nebivolol may be of particular benefit to certain subgroups of hypertensive patients, especially those with comorbidities such as heart failure with reduced ejection fraction (HFrEF), coronary artery disease, and atrial fibrillation.* With its dual mechanism of action of beta1 selectivity and nitric oxide-mediated vasodilatory effects, the beta-blocker nebivolol may overcome concerns with older generation beta-blockers.

*The approved indications for nebivolol are hypertension and heart failure.

Benefit A Real World Study
Though randomized controlled trials are the gold standard for establishing treatment efficacy and safety, stringent inclusion criteria of RCTs often lead to the enrolment of a homogenous study population that limits the generalizability of findings to routine clinical practice. Therein lies the value of real-world studies, which can provide data to support treatment decisions and monitor post-market adverse events.

BENEFIT is a large, prospective, observational study which evaluated nebivolol’s efficacy and safety in hypertensive patients in a real-world setting.14 Conducted at 66 sites in South Korea, the study included over 3000 patients. The primary efficacy end point was the change in systolic and diastolic BP after 12 and 24 weeks of treatment with nebivolol 5 mg once daily, while secondary efficacy end points included the change in heart rate from baseline after 12 and 24 weeks.14

Nebivolol significantly decreased mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 12 weeks (SBP: 10.2 ± 19.9 mm Hg; p<0.0001, DBP: 6.0 ± 13.6 mm Hg; p<0.0001), and at 24 weeks (SBP 11 ± 20.6 mm Hg; p<0.0001, DBP 6.6 ± 13.8 mm Hg; p<0.0001) compared with baseline (Figure 2).14 The secondary end point was also met; heart rate significantly decreased after 12 weeks (6.3 ± 13.4 bpm; p<0.0001) and 24 weeks (6.4 ± 13.4 bpm; p<0.0001) compared with baseline.14

Benefit Fig02
Secondary analysis of the primary end points was performed in subpopulations of patients who were assigned according to nebivolol use:

de novo (n =321), for newly diagnosed patients not on prior therapy;

monotherapy switch (n=266), for patients taking a single antihypertensive agent at study entry who switched to nebivolol during the study;

combination switch (n=1044), for patients on combination antihypertensive therapy who had switched one medication to nebivolol during the study, and

add-on (n=1167), for patients taking a single antihypertensive agent at study entry who received add-on nebivolol during the study.14

The subpopulation analysis showed significant reductions in SBP and DBP from baseline at 12 weeks and 24 weeks in all subgroups analyzed (p<0.0001) (Figure 3).14

Benefit Fig03
The majority of adverse events were mild and moderate. The adverse drug reactions were comparable to those in previous reports, with dizziness (0.2%), bradycardia (0.2%) and dyspnoea (0.1%) being the most common. There were also no new safety signals.14

Overall, the BENEFIT study provides real-world evidence that once daily nebivolol is efficacious and safe when used as a monotherapy or as an add-on therapy in Korean hypertensive patients with or without comorbidities. These findings are in line with previous studies, including those conducted in patients of various ethnicities, and confirms existing evidence for nebivolol’s role in BP control.

Q. Do the benefits of nebivolol apply to the elderly? Or is there any evidence of reduced efficacy or safety in older populations?
 Clinical experience suggests that nebivolol 5 mg once daily is suitable for older patients. Studies have shown no significant difference in the efficacy and safety of nebivolol among age groups, including the elderly.15 In addition, compared with younger patients, the elderly has relatively more comorbidities such as left ventricular dysfunction, atrial fibrillation and coronary artery disease, which may serve as compelling indications for beta-blockers. Vasodilating beta-blockers such as nebivolol are ideal, as they preserve cardiac output and increase stroke volume.

Q. Can nebivolol be used with PDE5 inhibitors or nitrates?
A. There is no absolute contraindication to use nebivolol with PDE5 inhibitors or nitrates, but bearing in mind that nebivolol stimulates endothelial nitric-oxide release to affect vasodilation; used together, it may have an additive effect. Therapy has to be individualized and precautions taken to avoid concurrent administration. If the patient experiences a severe drop in BP when using both medications, then the timing of the intervals between administration should be lengthened. Notably, unlike other beta-blockers, nebivolol has a vasodilatory effect which maintains sexual function in men,4,13 reducing the risk of erectile dysfunction and the subsequent need for PDE5 inhibitors.

Q. There are concerns over beta-blockers having adverse effects on metabolic profile (including blood glucose and lipids), which may impact cardiovascular outcomes in the long term. Is this the case for nebivolol?
A. Studies have shown that nebivolol does not have an adverse impact on metabolic profile.12

Q. Can you share your clinical experience of using nebivolol combined with other antihypertensives (eg, ARBs)?
A. For patients with coronary artery disease or atrial fibrillation, combining a beta-blocker like nebivolol and an ARB would be quite ideal. Clinical and real-world evidence has shown benefits in these subsets of patients.

Q. What is the effect of nebivolol in the male vs female population? Is there any difference in effect shown in the BENEFIT trial?
Vasodilating beta-blockers such as nebivolol are also particularly beneficial for women as they are more prone to microvascular disease, and develop diastolic dysfunction and diastolic heart failure. We are still awaiting the analysis and publication of the data from the BENEFIT trial.

Q. Can vasodilating beta-blockers be used in patients with chronic obstructive pulmonary disease (COPD)?
A. Yes. In fact, they can be life-saving for COPD patients, as COPD patients die more often from cardiovascular causes than of pulmonary causes, and one of the main reasons is the underutilization of beta-blockers. COPD patients are bombarded with long-acting beta agonists, which increases heart rate and can trigger ischaemic events and may develop acute coronary syndromes. Beta-blockers can prevent this.
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