Abstract & Commentary
Synopsis: Atenolol is unsuitable as a first-line drug in hypertension.
Source: Carlberg B, et al. Atenolol in Hypertension: Is It a Wise Choice? Lancet. 2004;364:1684-1689.
Atenolol is widely used as a first-line therapy for hypertension because it is beta 1 selective and it has low lipophilicity, which should result in fewer central nervous system side effects. However, recent studies have questioned its effectiveness. Thus, Carlberg and colleagues reviewed available randomized, controlled trials of atenolol in hypertension that evaluated morbidity and mortality. They identified 4 studies that compared atenolol to placebo or no treatment, and 5 that compared it to other drugs. The 4 placebo controlled trials encompassing 6825 patients followed for a mean of 4.6 years showed major differences in blood pressure, as expected by no difference in outcome vs placebo: all cause mortality RR = 1.01; cardiovascular mortality .99; and myocardial infarction .99. The risk of stroke showed a trend downward on atenolol (RR, 0.85; CI, .72-1.01). In the 5 drug comparison trials encompassing 17,671 patients followed for 4.6 years on average, atenolol was equally effective at lowering blood pressure, but demonstrated a higher mortality (RR, 1.3; CI, 1.02-1.25) and more strokes (RR, 1.3; CI, 1.12-1.50), as compared to other non-beta blocker drugs. Carlberg et al concluded that atenolol is unsuitable as a first-line drug in hypertension.
Comment by Michael H. Crawford, MD
These provocative results cast doubt on the use of atenolol as a first-line antihypertensive agent. What could explain these findings? Atenolol is less lipophilic. Animal studies have shown that the amount of beta-blocker in the central nervous system correlates with anti-ventricular fibrillation effects. Studies of metoprolol, propranolol, and timolol, which are more lipophilic, have shown reductions in mortality. Also, atenolol is beta 1 selective, but so is metropolol and others. In addition, the effects of atenolol on left ventricular hypertrophy have not been characterized. Finally, atenolol does not improve endothelial function in hypertensives.
There are some issues with this analysis. First, few trials have compared different beta blockers in hypertension. Those that used different beta blockers considered them as a group and did not break down the results with regards to the different beta blockers. So, this analysis compares results from studies using various beta blockers alone or versus other classes of antihypertensive agents, as well as studies where not all the patients were hypertensive, such as post myocardial infarction trials. Second, Carlberg et al are from Sweden, as is metoprolol. Perhaps there is some nationalistic bias here, since metoprolol is the only other beta 1 selective agent readily available in the United States. Third, atenolol is usually given once a day to be competitive with other agents, but its half life doesn’t really support this dosing frequency. It should probably be given twice a day. Metoprolol, on the other hand, now comes in a sustained release form (Toprol XL), which permits once a day dosing despite its relatively short half life. Many comparison drug trials suffer from not using comparative doses or dosing strategies; comparing different studies compounds this problem even more.
Regardless of these concerns, the data are provocative. The fact that placebo controlled trials of atenolol for hypertension showed no mortality benefit is disturbing, since we have several other agents that have been shown to reduce mortality (eg, ACE inhibitors and angiotensin receptor blockers). Thus, Carlberg et al make a cogent point that perhaps atenolol should not be considered first line monotherapy for hypertension.
Dr. Crawford is a Professor of Medicine and the Chief of Clinical Cardiology at the University of California, San Francisco.