Umea, Sweden - A new meta-analysis has raised doubts about the suitability of atenolol as a first-line antihypertensive drug and as a reference drug in outcome trials of hypertension.[1]

The analysis, published in the November 6, 2004 issue of the Lancet, was conducted by three Swedish doctors led Dr Bo Carlberg (Umea University Hospital, Sweden). They note that questions have been raised about the suitability of beta blockers as first-line treatment options in hypertension. For example, in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, losartan was shown to be more effective than atenolol, but whether this result was due to a beneficial effect of losartan or a weak effect of atenolol on cardiovascular disease—or both—has been debated, they comment. The researchers also point out that the effect of atenolol post-MI has been questioned.

Carlberg et al therefore set out to systematically review the effect of atenolol on cardiovascular morbidity and mortality in hypertensive individuals. They reviewed randomized controlled trials that assessed the effect of atenolol on cardiovascular morbidity or mortality in patients with primary hypertension. They identified four studies that compared atenolol with placebo or no treatment (comprising 6825 patients who were followed up for a mean of 4.6 years) and five studies that compared atenolol with other antihypertensive drugs (comprising 17 671 patients who were followed up for a mean of 4.6 years).

Results of this meta-analysis showed that despite major differences in blood-pressure lowering, there were no differences between atenolol and placebo on all-cause mortality, cardiovascular mortality, or MI. But there was a lower risk of stroke with atenolol vs placebo. When atenolol was compared with other antihypertensives, there were no major differences in blood-pressure lowering between the treatment arms, and atenolol showed significantly higher rates of all-cause mortality, cardiovascular mortality, and stroke.

Noting that the blood-pressure-lowering effect of atenolol is similar to other antihypertensive drugs, the researchers suggest that other characteristics of atenolol probably explain the findings of this meta-analysis. They list these other characteristics as follows:

1. Atenolol differs from other beta blockers in its low lipophilic profile. Animal studies suggest that the ability to prevent ventricular fibrillation depends on the amount of beta blocker in the central nervous system, with the hydrophilic atenolol having very low permeability into the nervous system.
2. Beta blockers seem to have less beneficial effect on regression of left ventricular hypertrophy than other antihypertensive drugs.
3. Many antihypertensive drugs correct the remodeling and endothelial dysfunction of small arteries seen in hypertension, but this has not been observed for atenolol. In a recent study, when patients on atenolol were switched to an angiotensin-1-receptor blocker, the arterial media/lumen diameter of resistance arteries decreased and endothelium-dependent relaxation increased.

Carlberg commented to heartwire that he would be reluctant to extrapolate these findings to other beta blockers. "We haven't studied other beta blockers. We chose atenolol because this is the most widely used beta blocker in hypertension and it has been the comparator in many studies. Atenolol is slightly different from other beta blockers, and the only firm conclusion we can reach is that atenolol shouldn't be used first line. We are not writing off all the others at this point," he said. But he added that these latest findings might question the efficacy of losartan to some degree, as the LIFE study used atenolol as the comparator.