Shah et al. demonstrated that carvedilol, a vasodilating beta-blocker, reduced augmentation index to a greater extent than beta-selective therapy with atenolol, which was actually associated with an increase in augmentation index (carvedilol ?0.68 % vs. atenolol 4.47 %; P = 0.04) [35•]. Similar results were seen in a study that compared the use of nebivolol, a vasodilating beta-blocker, with metoprolol in 80 patients with hypertension . Results after one year demonstrated no difference in brachial blood pressure reduction but a greater decrease in central systolic blood pressure (P = 0.07) and central pulse pressure (P = 0.004) in subjects treated with nebivolol [36••]. A reduction in left ventricular mass quiver phone number was observed in the nebivolol arm although no comparison was made with the metoprolol arm; there was no difference in the augmentation index between the two arms of the study [36••]. Another study demonstrated reductions in the augmentation pressure and augmentation index with nebivolol versus atenolol . In that study, change in heart rate was inversely related to augmentation pressure (r = ?0.56, P < 0.001) and augmentation index.
Insight from short-term studies of the impact of beta-blockers and reduction in heart rate on central blood pressure and augmentation may provide an explanation of differing results from long-term clinical trials that include beta-blockers. As a result of effects on central blood pressure, studies in which beta-blockers are compared to antihypertensives, which also lower heart rate, may be more likely to report similar outcomes, whereas beta-blockers may have increased cardiovascular event rates when compared to antihypertensive regimens that do not lower heart rate. In the INVEST trial, over 20,000 patients with coronary artery disease were randomized to verapamil or atenolol based therapy . At 24 months, there was no difference in blood pressure control or the rate of the primary cardiovascular composite . It is noted that despite verapamil’s negative chronotropic effects, heart rate was lower at 24 months in the atenolol arm (69.2/min vs. 72.8/min, P < 0.01) . Similar results were seen in the NORDIL study, in which there was no difference in the composite of stroke, myocardial infarction, or cardiovascular death among patients assigned to diltiazem or atenolol-thiazide based treatments . It's possible that the results in these trials comparing beta-blockade and calcium channel blockade are due to relatively similar effects of both classes on heart rate and peripheral and central blood pressure.
On the other hand, when beta-blockers are compared to agents that do not lower heart rate such as angiotensin receptors blockers, diuretics, and dihydropyridine calcium channel blockers, beta-blockers have been associated with increased rates of cardiovascular events. A few of these trials will be reviewed here. The LIFE trial evaluated the effect of losartan versus atenolol in 9,193 patients with hypertension, and demonstrated decreased rates of cardiovascular disease and stroke in subjects randomized to losartan . The Medical Research Council (MRC) trial assigned hypertensive patients with a diastolic blood pressure < 115 mmHg to a diuretic, atenolol, or placebo pared to placebo, treatment with a diuretic was associated with decreased risk for stroke, coronary heart disease, cardiovascular events, and cardiovascular death. No differences were observed between the atenolol and placebo groups . In the ASCOT trial, lower rates of the primary cardiovascular outcome, stroke, cardiovascular events and procedures, and all-cause mortality were observed in the amlodipine adding perindopril arm versus the atenolol adding a diuretic arm [42•]. The lower rate of adverse outcomes with amlodipine was independent of baseline heart rate indicating that, based on ASCOT, an elevated heart rate is not an indication for choosing a beta-blocker for management of hypertension [42•]. The ASCOT evaluation of central blood pressure provides a potential explanation for these results, and is reviewed below. The increased rate of cardiovascular events in the atenolol arms of the LIFE, MRC, and ASCOT trials may be due to lowering of heart rate, which may increase augmentation pressure and central blood pressure . However, it is worth stating again that the beta-blocker used was atenolol, which is known to have an adverse side effect and metabolic profile .