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doi: 10.1097/ALN.0000000000000195

Does β Selectivity Really Affect Outcome?

Wicker, Jordan Field M.D.; Bronheim, David M.D.

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To the Editor:

We read with great interest the October 2013 article1 entitled “Selective β1-Antagonism with Bisoprolol is Associated with Fewer Postoperative Strokes than Atenolol or Metoprolol,” where the authors describe a decrease in the risk of stroke in patients receiving bisoprolol versus those receiving the less selective β-antagonists, atenolol and metoprolol. Although the results are noteworthy, it remains unclear to us that the outcomes reflect relative β selectivity. Previously published studies have demonstrated an association between the time of initiation of β-blocker therapy and outcome, with higher morbidity and mortality being associated with the initiation of β-blockade nearer the time of surgery. Flu et al.2 showed significantly fewer cardiovascular events as well as significantly lower mortality in patients who were initiated on β-antagonists more than 1 week preoperatively compared with that in patients who were initiated on β-antagonists less than 1 week before surgery. Ellenberger et al.3 in a 2011 issue of ANESTHESIOLOGY, a study in which the author of this article was an active participant, similarly described worse outcomes in patients receiving acute β-blockade in comparison with the outcomes in patients receiving chronic therapy. In this current study, the authors note the lack of evidence of β-blocker usage in 35% of their patients before hospitalization, which was consistent with their previous data demonstrating that approximately 30% of their patients were started on β-antagonists between the time of admission and surgery. Unfortunately, they failed to quantify in the published article whether metoprolol, atenolol, and bisoprolol usage were proportionately similar in this higher-risk group. One may speculate or perhaps even assume that in anticipation of the need for intravenous β-blocker therapy perioperatively, these 30% of patients, whose outcomes are predictably worse, would be much more likely to receive either metoprolol or atenolol. Both of these have an intravenous formulation; bisoprolol does not. The authors even comment that only a small number of patients received more than one of these drugs, suggesting that our assumption is in fact correct. With this as a premise, we wonder whether this bias for initiating therapy near the time of surgery with metoprolol and atenolol versus bisoprolol was the reason behind the higher stroke rate and not differences in cerebral blood flow occurring as a consequence of β-receptor selectivity. Fortunately, the relative effects of β selectivity versus time of initiation could be clarified either by removing all patients not on chronic therapy from the analysis or by demonstrating no relation between time of initiation of β-blocker therapy and choice of medication.
Furthermore, in this published study, the average dosages of β-blockers given are not noted. This is relevant because the PeriOperative ISchemic Evaluation (POISE) study4 demonstrated that hypotension secondary to metoprolol was associated with an increased incidence of stroke. In the POISE study, the dosages of metoprolol given were relatively high. In contrast, Wallace et al.5 demonstrated that lower doses of metoprolol proved to have better outcomes, so a comparison of the relative doses of β-blockers may be relevant.
Finally, one can just as easily speculate that metoprolol’s variable metabolism, which may result in relative overdosing or underdosing, may be the cause of the differences and not its β selectivity.6
Although we have concerns that this study does not truly demonstrate the advantages of β selectivity, others have demonstrated improvements in outcomes with bisoprolol when given well before the perioperative period.7 Also, as demonstrated in this study, Wallace et al.8 have also noted the relative advantages of atenolol versus metoprolol. Many have assumed that these differences in outcomes were related to the initiation of therapy and the variable metabolism of metoprolol. The authors’ suggestion that β selectivity alone may be the source of improvement clearly warrants further investigation.
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Competing Interests

The authors declare no competing interests.
Jordan Field Wicker, M.D., David Bronheim, M.D.
Mount Sinai School of Medicine, New York, New York (D.B.).
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1. Ashes C, Judelman S, Wijeysundera DN, Tait G, Mazer D, Hare GMT, Beattie WS. Selective β1-antagonism with bisoprolol is associated with fewer postoperative strokes than atenolol or metoprolol. ANESTHESIOLOGY. 2013;119:777–87

2. Flu WJ, Kuijk JP, Chonchol M, Winkel TA, Verhagen HJM, Bax JJ, Poldermans D. Timing of pre-operative beta-blocker treatment in vascular surgery patients: Influence on post-operative outcome. J Am Coll Cardiol. 2010;56:1922–9

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4. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Malaga G, Avezum A, Chan M, Montori VM, Jacka M, Choi P. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): A randomised controlled trial. Lancet. 2008;371:1839–47

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6. Nagele P, Liggett SB. Genetic variation, β-blockers, and perioperative myocardial infarction. ANESTHESIOLOGY. 2011;115:1316–27

7. Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, Baars HF, Yo TI, Trocino G, Vigna C, Roelandt JR, van Urk H. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341:1789–94

8. Wallace AW, Au S, Cason BA. Perioperative β-blockade: Atenolol is associated with reduced mortality when compared to metoprolol. ANESTHESIOLOGY. 2011;114:824–36

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