It was almost a year ago that we discussed the findings of the POISE trial (see November 20, 2007 Patient Safety Tip of the Week “New Evidence Questions Perioperative Beta Blocker Use”). The POISE trial showed that, though preoperative beta blockers prevented 15 MI’s for every 1000 patients treated, there was an increased risk of stroke and an excess of 8 deaths per 1000 patients treated. Many hospitals have been slow to change their perioperative beta blocker policies despite those significant findings.
Now a new study (Kaafarani 2008) adds additional concerns about the use of beta blockers in patients undergoing noncardiac surgery. However, it raises more questions than it answers.
The study, conducted at a VA medical center, identified all patients in one year who were taking beta blockers during noncardiac surgery. The authors then matched these patients with a control group from the same population undergoing noncardiac surgery. They found that the patients on beta blockers had higher rates of 30-day MI (2.94% vs, 0.74%) and 30-day mortality (2.52% vs. 0.25%). Differences for both rates were statistically significant.
In addition, within the beta blocker group the mean pre-op heart rate was higher in those patients who died compared to those who survived. Note that all the deaths were in patients considered intermediate or low cardiac risk and no patients in the high risk group died. Thus, this study particularly raises the possibility that beta blockers may be detrimental in low-risk or intermediate-risk patients. It also raises the possibility that inadequate beta blockade (as determined by pre-op heart rate) may play a role in the higher risk for mortality and that titration of beta blockers to an acceptable heart rate before surgery may be important. They suggest the heart rate of 50-60 per minute recommended in the AHA/ACC guidelines might be the most appropriate target.
The Kaafarani study adds weight to the POISE trial in that it reaches the similar conclusion that beta blockers increase mortality after surgery. It differs from the POISE trial in that most of the patients were already on beta blockers well before their surgery (in POISE the beta blockers were begun immediately before surgery). Yet it still leaves open a possibility raised by critics of POISE: that slow titration of beta blockers to achieve a target heart rate might result in a beneficial effect of beta blockers in the perioperative period.
But there are problems with this study. It was not a randomized controlled trial. Rather the “control” group was constructed to look like the patients in the beta blocker group in most respects. Todd Rasmussen, author of the invited critique of the Kaafarani paper, suggests it is possible, if not likely, that the beta blocker patients were at higher risk than the control group in view of the fact that their physicians began them on beta blockers. Also, the reasons for beta blocker use were not specified in the Kaafarani paper. That is important because another recent paper (Bangalore 2008), a systematic review, showed that use of beta blockers for hypertension increased the risks for MI, stroke and mortality. In fact, in hypertensive patients on beta blockers, the risks increased in proportion to the degree of heart rate slowing achieved. The latter fact certainly makes the controversy over target heart rate even more muddled.
So does the Kaafarani study add any practical advice? It certainly does suggest that perioperative beta blockers should not be started without really good indications. Even though the AHA/ACC guidelines suggest a benefit for perioperative beta blockers in high-risk patients, their use had in practice extended to intermediate- and low-risk patients as well. That was the group that did particularly poorly in the Kaafarani study. High-risk patients would be, for example, patients who had demonstrated myocardial ischemia on preoperative cardiac testing. Also, most would also argue that sudden withdrawal of beta blockers is probably not appropriate in the perioperative period so discontinuing them immediately before surgey would not appear to be wise.
What is clearly needed is a randomized controlled trial, similar to POISE, in which patients are clearly stratified by cardiac risk and beta blockade is achieved by slower titration and to target heart rates. Until then the impact of perioperative beta blockers will remain speculative.
Update (11/13/08): Today’s online edition of The Lancet contains a new meta-analysis of 33 studies on perioperative beta blockers in patients having non-cardiac surgery (Bangalore 2008b). This paper concludes that evidence does not support the use of beta blocker therapy for the prevention of perioperative clinical outcomes in patients undergoing non-cardiac surgery. It does acknowledge that the “anti” trials are heavily weighted by the POISE trial results, whereas the “pro” trials are heavily weighted by the early trials in mainly higher risk patients. Their conclusion is that beta blockers should not be used routinely for the perioperative treatment of patients undergoing non-cardiac surgery unless patients are already taking them for other clinically indicated reasons (MI, CAD, CHF). They do acknowledge there are issues still unresolved about types of beta blockers, dosages, protocols, etc. and suggest those issues need to be evaluated in appropriate randomized controlled trials. An accompanying editorial (Boersma 2008) by the investigators of previous pro-beta-blocker trials again raises the issues of the importance of hemodynamic factors related to dose, duration and timing of the perioperative beta blockers.
Update: See also our November 2010 What’s New in the Patient Safety World column “More Perioperative Beta Blocker Controversy”
Kaafarani HMA, Atluri PV, Thornby J, Itani KMF. β-Blockade in Noncardiac Surgery: Outcome at All Levels of Cardiac Risk. Arch Surg. 2008;143(10):940-944
Rasmussen TE. β-Blockade in Noncardiac Surgery—Invited Critique. Arch Surg. 2008;143(10):944
Bangalore S, Sawhney S, Messerli FH. Relation of Beta-Blocker–Induced Heart Rate Lowering and Cardioprotection in Hypertension. J Am Coll Cardiol 2008 52: 1482-1489
Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH. Perioperative β blockers in patients having non-cardiac surgery: a meta-analysis. The Lancet, Early Online Publication, 12 November 2008
Boersma E, Poldermans D. β blockers in non-cardiac surgery: haemodynamic data needed. The Lancet, Early Online Publication, 12 November 2008