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.
WHY WERE THE RESULTS SO DISAPPOINTING?
Problems with atenolol
Most of the trials in the meta-analyses discussed above used atenolol and other beta-blockers that had no vasodilatory properties.
Further, in most of the trials atenolol was used in a once-daily dosage, whereas ideally it needs to be taken more frequently, based on its pharmacokinetic and pharmacodynamic properties (a half-life of 6–9 hours).3 Neutel et al28 confirmed that atenolol, when taken once daily, leaves the patient unprotected in the last 6 hours of a 24-hour period, as demonstrated by 24-hour ambulatory blood pressure monitoring. It is possible that this short duration of action of atenolol may have contributed to the results observed in clinical trials that used atenolol to treat hypertension.
Differences between older and younger patients
Another possible reason for the disappointing results is that the trials included many elderly patients, in whom beta-blockers may not be as effective. The pathophysiology of hypertension in younger people is different from that in older patients.29 Hemodynamic characteristics of younger hypertensive patients include a high cardiac output and hyperdynamic circulation with a low pulse pressure, while older patients have lower arterial compliance with an elevated vascular resistance.
The notion of choosing antihypertensive medications on the basis of age and age-related pathophysiology is supported by several clinical studies. Randomized controlled trials appear to show that beta-blockers are effective in younger hypertensive patients.30
Conversely, the CAFE (Conduit Artery Function Evaluation) trial,31 a substudy of the main ASCOT trial,26 indicated that betablocker-based therapy was less effective in reducing central aortic pressure than were regimens based on an ACE inhibitor or a calcium channel blocker.
The CAFE researchers recruited 2,073 patients from five ASCOT centers and used radial artery applanation tonometry and pulse-wave analysis to derive central aortic pressures and hemodynamic indices during study visits up to a period of 4 years. Although the two treatment groups achieved similar brachial systolic blood pressures, the central aortic systolic pressure was 4.3 mm Hg lower in the amlodipine group (95% CI 3.3–5.4; P < .0001), and the central aortic pulse pressure was 3.0 mm Hg lower (95% CI 2.1–3.9; P < .0001).
Pulse-wave dyssynchrony
Bangalore et al47 offer an interesting hypothesis to explain the probable adverse effect of beta-blockers. Their theory concerns the effect of these drugs on the arterial pulse wave.
Normally, with each contraction of the left ventricle during systole, an arterial pulse wave is generated and propagated forward to the peripheral arteries. This wave is then reflected back to the heart from the branching points of peripheral arteries. The final form of the pressure wave at the aortic root is a synchronized summation of the forward-traveling wave and the backward-reflected wave.
In healthy people with normal arteries, the reflected wave merges with the forward-traveling wave in diastole and augments coronary blood flow. In patients whose arteries are stiff due to aging or vascular comorbidities, the reflected wave returns faster and merges with the incident wave in systole, resulting in higher left ventricular afterload and less coronary perfusion.48
Bangalore et al47 propose that artificially reducing the heart rate with beta-blockers may further dyssynchronize the pulse wave, adversely affecting coronary perfusion and leading to an increased risk of cardiovascular events and death.
Metabolic side effects
Older beta-blockers, and especially atenolol, have well-known metabolic adverse effects, particularly impairment of glycemic control. This adverse effect appears to occur only with beta-blockers that do not possess vasodilatory properties and thus increase peripheral vascular resistance, which results in lower glucose availability and reduced uptake by skeletal muscles.49
Bangalore et al50 evaluated the effect of beta-blockers in a meta-analysis of 12 studies in 94,492 patients followed up for more than 1 year. Beta-blocker therapy resulted in a 22% higher risk of new-onset diabetes mellitus (RR 1.22, 95% CI 1.12–1.33) than with other nondiuretic antihypertensive agents.
Of note, however, the meta-analysis did not show a significantly higher risk of the onset of diabetes with propranolol or metoprolol than with other nondiuretic antihypertensives when studies of these beta-blockers were separated from atenolol-based studies.
Further, the United Kingdom Prospective Diabetes Study40 found that cardiovascular outcomes in patients with good blood pressure control were similar when atenolol-based therapy was compared with therapy with the ACE inhibitor captopril (Capoten).
A meta-analysis conducted by Balamuthusamy et al51 in 2009 found no higher risk of stroke in patients with hypertension and diabetes mellitus who received beta-blockers than in those who received other antihypertensive medications. However, beta-blockers were associated with a higher risk of death from cardiovascular causes (RR 1.39, 95% CI 1.07–1.804; P < .01) compared with reninangiotensin blockade.
