Physiologic disturbances associated impaired elimination of drugs and their metabolites is common in older patients with chronic kidney disease. In a recent article published in AJKD, Fleet et al performed a population-based matched retrospective observational investigation in 75,257 older patients (mean age, 75 years) recently initiated oral atenolol or metoprolol tartrate. The study examined 90-day adverse events and mortality, and whether adverse events in the groups differed by baseline kidney function.

Atenolol, a β1-selective β-blocker, is one of the first drugs in this class.  It was introduced in the 1970s and is used to control hypertension. Recent hypertension guidelines have dropped β-blocker from the “first-line” category, but their use continues to be prevalent. The traditional teaching is that atenolol, a water-soluble β-blocker, is highly dependent on renal elimination, and prescribing guidelines recommend lower doses and careful monitoring in CKD patients to avoid side effects related to drug accumulation. Metoprolol tartrate on the other hand, is a lipid soluble drug metabolized by the liver, with less accumulation at lower levels of kidney function.

In this study, Fleet et al hypothesized that initiating oral atenolol treatment compared to metoprolol tartrate would be associated with a greater likelihood of adverse events, including mortality in the first 90 days of treatment. They also postulated that compared to metoprolol tartrate, atenolol risk is greatest in patients with lower eGFRs. Contrary to their original hypothesis, the authors found that atenolol was associated with lower 90-day risk of mortality than metoprolol tartrate (incidence, 0.97% vs 1.44%; relative risk, 0.68; 95% CI, 0.61-0.74). There was no difference between atenolol and metoprolol tartrate in the risk of composite adverse outcome of 90-day hospitalization with bradycardia or hypotension (incidence, 0.71% vs 0.79%; RR, 0.90; 95% CI, 0.80-1.01). Although the mortality and adverse event risk was higher at lower eGFR, atenolol continued to be associated with lower risk compared to metoprolol tartrate.

In a post hoc analysis, atenolol was associated with lower risk of hospitalization for myocardial infarction by 16%, and for ventricular arrhythmia by 65%.

Of note, patients with end-stage renal disease were excluded because both drugs are dialyzable. Additionally, only a small percentage of patients (1.5% of n=13,847) in each treatment group had severely reduced eGFRs below 30 mL/min/1.73 m². The authors postulate that patients in the atenolol group may derived benefit from higher plasma β-blocker concentration. A higher concentration β-blocker may be particularly beneficial for patients with coronary artery disease, congestive heart failure, left ventricular hypertrophy, and arrhythmias. While the above mechanism is plausible, information on the heart rate was not available in this study; this would have provided useful information on the degree of β-blockade in these patients.

This study highlights that pharmacokinetic data alone may not predict clinical outcomes in older patients with CKD. While only a randomized control trial would be able to confirm or reject the findings in this study, conducting such a trial is challenging and unlikely to be performed. In the absence of such data, what should we conclude given the results of this current study? When a β-blocker is indicated in an older patient with moderately reduced kidney function, atenolol may be preferred over metoprolol tartrate. Of course, physicians are encouraged to start low and go slow in older patients with reduced kidney function while carefully monitoring heart rate and blood pressure. Is this what you would conclude? Please share your thoughts!

Abdo Asmar, MD
eAJKD Advisory Board Member

To view the article abstract or full-text (subscription required), please visit AJKD.org.