Beta-blockers for hypertension: Are they going out of style?
ABSTRACTAlthough beta-blockers lower blood pressure in most patients, the outcomes of clinical hypertension trials of these drugs have been disappointing, and the value of beta-blockers in treating hypertensive patients who do not have compelling indications for them has been questioned. Until these drugs are proved beneficial, they should be used as antihypertensive therapy only in patients with compelling cardiac indications for them or as add-on agents in those with uncontrolled or resistant hypertension.
KEY POINTS
- No evidence exists that beta-blockers prevent first episodes of cardiovascular events in patients with hypertension, and in some trials, outcomes were worse with beta-blockers than with antihypertensive drugs of other classes.
- Younger hypertensive patients have hemodynamic characteristics that would seem to be amenable to beta-blocker therapy. However, most clinical trials of beta blockers did not stratify patients by age.
- Most trials of the antihypertensive effects of beta-blockers used atenolol (Tenormin), which is not an ideal representative of this class of drugs.
- Newer beta-blockers with vasodilatory properties may overcome the adverse effect of increased peripheral vascular resistance that occurs with older agents such as atenolol.
NEWER BETA-BLOCKERS MAY BE BETTER
In the United States, more than 40 million prescriptions for atenolol are written every year, making it by far the most commonly used beta-blocker for the treatment of hypertension. 52 It is clear, however, that atenolol is not an ideal representative of this class of antihypertensive medications.
Preliminary data from studies of newer beta-blockers that possess beneficial vasodilatory properties are encouraging. Animal studies and preliminary human studies find that these new-generation beta-blockers cause fewer adverse metabolic effects and improve endothelial function, measures of arterial stiffness, and cardiovascular outcomes.
Carvedilol
Carvedilol is a nonselective beta-blocker with vasodilatory effects that are thought to be due to its ability to concurrently block alpha-1 receptors in addition to beta receptors. 53 In experiments in vitro and in trials in patients with diabetes and hypertension, carvedilol increased endothelial vasodilation and reduced inflammation and platelet aggregation. These effects may be achieved though antioxidant actions, thereby preserving nitric oxide bioactivity.54,55
In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial,56 carvedilol was associated with better maintenance of glycemic control in diabetic hypertensive patients than was metoprolol. Insulin sensitivity improved with carvedilol but not with metoprolol, and fewer patients on carvedilol progressed to microalbuminuria.
Nebivolol
Nebivolol is a novel selective beta-blocker with a much higher affinity for beta-1 adrenergic receptors than for beta-2 adrenergic receptors. Among all the beta-blockers in clinical use today, nebivolol has the highest selectivity for beta-1 receptors.8
Nebivolol causes vasodilation through activation of the l-arginine/nitric oxide pathway.57–59 Blockade of synthesis of nitric oxide leads to local arterial stiffness. Endothelial dysfunction is characterized by decreased bioavailability of nitric oxide and has been shown to be a strong predictor of cardiovascular outcomes. By generating nitric oxide, nebivolol reduces peripheral vascular resistance, overcoming a significant side effect of earlier beta-blockers that lowered blood pressure but ultimately increased peripheral vascular tone and resistance.8
In an experiment in a bovine model,60 nebivolol significantly reduced the pulse-wave velocity (a measure of arterial stiffness), while atenolol had no effect. Moreover, evidence for the role of the l-arginine/nitric oxide pathway in the vasodilatory effect of nebivolol was demonstrated by co-infusion of NG-monomethyl-L-arginine, a specific endothelial nitric oxide synthetase inhibitor that attenuated the reduction of pulse-wave velocity by nebivolol.
In studies in hypertensive patients, nebivolol was associated with a better metabolic profile than atenolol, with none of the adverse effects on insulin sensitivity that atenolol had.61 In the Study of Effects of Nebivolol Interventions on Outcomes and Rehospitalization in Seniors With Heart Failure (SENIORS) trial, significantly fewer patients receiving nebivolol died or were admitted to the hospital for cardiovascular reasons compared with those receiving placebo.62
Although these findings are encouraging, we do not yet know if these effects will translate into a significant reduction in cardiovascular outcomes in clinical trials. Large, prospective hypertension outcome trials, particularly to evaluate primary prevention of cardiovascular outcomes, are needed for an evidence-based approach to using the newer beta-blockers as preferred first-line therapy for hypertension.
WHAT RECENT GUIDELINES SAY ABOUT BETA-BLOCKERS
The British National Institute for Health and Clinical Excellence and the British Hypertension Society, in their 2004 guidelines, recommended beta-blockers as one of several first-line antihypertensive medications in young, nonblack patients.63 On the other hand, they advised clinicians to be aware of the reported increase in onset of diabetes mellitus in patients treated with these medications. After the LIFE24 and ASCOT26 study results were published, these guidelines were amended to exclude beta-blockers as preferred routine initial therapy for hypertension.64
More recently, the 2007 European Society of Hypertension and European Society of Cardiology reconsidered the role of beta-blockers, recommending them as an option in both initial and subsequent antihypertensive treatment strategies.65
The current guidelines from the National Heart, Lung, and Blood Institute,66 which were published in 2003, were highly influenced by the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),2 and favor diuretics as the first-line therapy. However, they indicate that beta-blockers are a suitable alternative, particularly when a compelling cardiac indication is present.53 We hope that the next update, expected late in 2009, will re-address this issue in the light of more recent data.
