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]
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 takeawaysβ-blockers retain an important place in the management of certain patient subgroups. The 2013 ESH/ESC guide-lines aﬃrm that β-blockers are suitable for ﬁrst-line or maintenance treatment of hypertension, either as monotherapy or in combination with other antihypertensive classes. Vasodilatory β-blocker nebivolol is more cardioselective than other β-blockers, with fewer undesirable side eﬀects. Nebivolol is not associated with bradycardia, adverse metabolic eﬀects, or sexual dysfunction, and reduces central pulse pressure and aortic stiﬀness better than atenolol or metoprolol. This makes nebivolol an ideal ﬁrst-line option for hypertension.
*ESH/ESC: European Society of Hypertension/European Society of Cardiology
**Nebivolol is not approved for congestive heart failure in Taiwan.