Optimizing hypertension management in clinical practice with nebivolol

Hypertension guidelines differ in their recommendation to use beta-blockers as first-line agents. At a Menarini-sponsored symposium held during the Asian Pacific Society of Cardiology Congress 2018 in Taipei, Taiwan, Professor Giuseppe Mancia from the University of Milano-Bicocca in Milan, Italy and Professor Jong-Won Ha from the Yonsei University College of Medicine in Seoul, Korea discussed the rationale behind these recommendations, and reviewed the role of beta-blockers in hypertension management, particularly the role of vasodilatory beta-blocker nebivolol (Nebilet®, Menarini). Professor Lin Jiunn-Lee, APSC 2018 chairman and president of the Taiwan Society of Cardiology, chaired the symposium.

Beta-blockers position in the hypertension guidelines

Beta-blockers (β-blockers) have been widely used as a first-step treatment for hypertension for many years. The WHO, the International Society of Hypertension, and the American guidelines all placed β-blockers, together with diuretics, as a first-step treatment for hypertension, said Mancia.

But more recently and for several reasons, β-blockers have been excluded as first-step treatment of primary hypertension in a number of guidelines and were relegated to second-line treatment or confined to specific indications. The 2017 American College of Cardiology/American Heart Association Task Force (ACC/AHA) guidelines recommend β-blockers only in patients with ischaemic heart disease or heart failure (HF). [Hypertension 2018;71:1269-1324] 

The Eighth Joint National Committee (JNC8) guidelines’ decision to drop β-blockers as a first-step treatment for hypertension was anchored on the LIFE study which showed that β-blocker use resulted in a higher rate of composite outcome vs an angiotensin receptor blocker (ARB). This was despite noting that β-blockers performed similarly to four other recommended drug classes in other studies. [Lancet 2002;359:995-1003]

In contrast, the 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines have maintained β-blockers as a first-step option for hypertension, together with diuretics, calcium channel blockers (CCBs), ACE inhibitors (ACEi), and ARBs, said Mancia. [Eur Heart J 2013;34:2159-2219]

What the RCTs tell us

Mancia, ESC chairperson and corresponding author of the ESH/ESC* guidelines, shared the rationale behind keeping β-blockers, either as a monotherapy or in combination with other drugs, for the treatment of hypertension. “There is no question about the beneficial effects of antihypertensive treatment in blood pressure (BP) lowering per se regardless of how it is obtained,” he said. A meta-regression analysis of 300,000 patients from different trials with different treatments showed that there was a linear relationship between BP reduction and the magnitude of beneficial effects despite differences in treatment. The extent of BP lowering is directly related to the reduction in stroke, chronic heart disease, HF, cardiovascular and all-cause death, regardless of the treatment agent used. [J Hypertens 2014;32:2285-2295; J Hypertens 2015;33:195-211]

“These findings suggest that BP lowering per se, rather than specific drug properties, reduces cardiovascular events,” said Mancia. “Therefore, antihypertensive agents should be assessed according to their ability to lower BP.”

In a meta-analysis of 357 randomized placebo-controlled trials, β-blockers lowered BP to a similar degree as diuretics, ACEi, ARBs, and CCBs. [Brit Med J 2003;326:1427] In another trial, CCBs had a greater preventive effect on stroke. [BMJ 2009;338:b1665]

“However, it is interesting to note that CCBs have persistently shown a reduced ability to protect against HF. [BMJ 2009;338:b1665; J Hypertens 2015;33:1321; Lancet 2015;387:957] This is the disadvantage of CCBs, but nobody ever mentioned this in the guidelines. This tells us that old drugs may have problems … and it’s not correct for guidelines to focus on just one problem and forget the others,” Mancia said. And just like any old drugs, β-blockers have quite a few inconveniences, he added.

“β-blockers are less effective against central blood pressure and in improving organ damage, have more side effects including sexual dysfunction, and dysmetabolic effects, including onset of type 2 diabetes. On the contrary, vasodilatory β-blockers, for example nebivolol, have favourable effects compared with conventional β-blockers,” said Mancia.

β-blockers: Where do they stand in 2018?

The ESH/ESC guidelines, in adopting the use of β-blockers as first-step treatment for hypertension, recognized that β-blockers are a heterogenous class, and cautioned against extrapolating effects of one agent to other agents within the class. [Blood Pressure 2009;18:308-347]

Most of the studies reporting lower effectiveness and unfavourable effects of β-blockers in hypertension therapy were on atenolol. [Lancet 2002;359:995-1003; Lancet 2004;364:1684-1689; Lancet 2005;366:1545-1553] “Not all β-blockers are equal,” said Ha. “Outcomes of these trials should be attributed specifically to atenolol, and not be construed as a class effect.”

Vasodilatory β-blockers such as nebivolol, carvedilol, or celiprolol appear not to share the limitations of the traditional β-blockers such as atenolol or metoprolol, he said. [Eur Heart J 2013;34:2159-2219; Blood Pressure 2009;18:308-347] “Nebivolol, for example, reduces central pulse pressure and aortic stiff ness better than atenolol or metoprolol and does not affect glucose tolerance compared with placebo,” said Ha. [Eur Heart J 2013;34:2159-2219]

Unique properties of nebivolol

Nebivolol is a third-generation β-blocker with the highest β₁-cardioselectivity and the highest β₁-/β₂-selectivity in its class, with no intrinsic sympathomimetic activity. [Br J Pharmacol 2001;133:1330-1338] In addition, nebivolol confers vasodilatory benefits that are mediated by the endothelial L-arginine/nitric oxide (NO) pathway. This dual mechanism of action underlies several haemodynamic qualities of nebivolol, which include reduction in heart rate, myocardial contractility, decreased peripheral vascular resistance (PVR), and improvements in systolic and diastolic function (Figure 1), explained Ha. [Vasc Health Risk Manag 2012;8:151-160; Heart Asia 2016;8:22-26]

“Unlike most β-blockers which are vasoconstrictive, nebivolol has vasodilating properties which help to increase cardiac output and stroke volume, while reducing peripheral resistance,” said Ha (Figure 2). [Drug Invest 1991;3:40-50] The vasodilating properties of nebivolol are a function of increased activity of endothelial NO synthase. NO contributes to vascular health and endothelial protection by inhibiting vascular inflammation, platelet aggregation, monocyte adhesion to endothelial cells, and abnormal smooth muscle cell proliferation. This makes nebivolol particularly suited for patients in whom NO-mediated endothelial dysfunction may be more pronounced, such as the elderly, the obese, and diabetic patients. [Vasc Health Risk Manag 2012;8:151-160]

Nebivolol:

Efficacy and safety

Nebivolol has been shown to be as effective as other antihypertensive agents (β-blockers, ACEi, ARBs, and CCBs) at reducing BP. Treatment with nebivolol resulted in similar reductions in BP as bisoprolol, atenolol, metoprolol, lisinopril, amlodipine, nifedipine retard, and enalapril, and significantly greater reductions in diastolic BP compared with losartan. [Drugs 2006; 66:1389-1409]

In terms of safety, nebivolol has fewer adverse effects compared with conventional β-blockers. Nebivolol is not associated with sexual dysfunction, bradycardia, reduced exercise capacity, or metabolic effects such as lipid and glucose dyshomeostasis. [Circulation 2011;123:2434-2506] A study comparing the effects of nebivolol and atenolol with and without chlorthalidone on sexual function in hypertensive men found that men treated with nebivolol maintained similar levels of sexual activity from baseline, whereas those on atenolol had significant reductions in sexual activity (Figure 3). [Clin Drug Invest 2005;25:409-416]

“The tolerability and side effect profile of an antihypertensive agent are of clinical importance as it impacts adherence,” Mancia said. “Adverse effects are the leading cause of non-adherence, discontinuation, or switching of treatment.” [J Hypertens 2000;18:1691-1699] Adherence to therapy also reduces the risk of coronary and cerebrovascular outcomes. [J Hypertens 2011;29:610-618; Hypertension 2015;66:742-749]

The right β-blocker for the right patient

In a world moving towards precision or personalized medicine, treatment should be contingent on drugs’ specific indications, said Mancia. “β-blockers are preferred in certain subpopulations and for specific conditions, for example, in patients with comorbidities, including angina pectoris, supraventricular tachyarrhythmias, ventricular arrhythmias, acute coronary syndrome, congestive heart failure** or previous MI; when ACEi or ARBs are not tolerated or contraindicated; in pregnant women, or women of childbearing age; and in those with evidence of increased sympathetic drive. In these patients, β-blockers may be used alone or as an add-on therapy to antihypertensive regimen.”

“While β-blockers generally provide comparable blood pressure reductions, nebivolol has the added advantage of enhanced vasodilation and blood fl ow by increasing the expression of endothelial NO synthase and beneficial haemodynamic effects such as increased stroke volume and preserved cardiac output,” said Ha. “Thus, nebivolol may be particularly suitable as a first-line treatment for hypertension.”

Key takeaways