Perioperative Betablockade: A Conundrum Still in Need of Study!

Résumé fourni par la source

Despite a number of studies over the past 30 or so years, there is still controversy over the best strategy for the perioperative approach to patients receiving intercurrent betablocking therapies. The article by Kertai et al1 makes an important contribution to the management of patients treated by betablockers (BBs) by drawing attention to the risk of their untimely withdrawal before surgery. Recent guidelines2,3 strongly recommend to maintain long-term betablockade in patients presenting for surgery. However, the supporting data are not very strong. It is legitimate to try to strengthen the recommendations and, at the same time, in view of the hypotension noted in PeriOperative ISchemic Evaluation (POISE) study,4 to obtain data on possible hazards attached to the maintenance of betablockade. The Quantum Clinical Navigation System Quality Assurance5 provided the database for such a study. A total of 410,288 cases with known BB therapy status as defined based on SCIP-Card-2 definition of pre/perioperative BB therapy were entered between 2009 and 2014. A total of 343,533 cases were not receiving BB therapy before admission, 3829 cases were receiving BB therapy before admission but did not receive perioperative BB therapy (withdrawn from BB therapy group), and 62,926 cases who were on BB therapy before admission also received perioperative BB therapy (continued on BB therapy group). After propensity matching, 3829 cases withdrawn from BB therapy and 15,316 cases continued on BB therapy were included in analyses. The conclusions are quite clear: withholding BBs in patients on long-term treatment increases 48 hours mortality of noncardiac surgery, but the price to pay in maintaining BBs is increased use of vasopressors and prolonged stay on the postoperative unit. The data analysis is strengthened by careful matching of patients in whom BBs were withheld with patients in whom they were maintained. As a large number of patients were included in the study, the statistical analysis is very convincing. Unfortunately, relying on the sheets as presented for the Quantum Clinical Navigation System Quality Assurance has limitations. First of all, the study is limited to the first 48 hours after surgery, instead of the more usual 30 days. The type of surgery is not available, and cardiovascular medication with the exception of BBs is not documented. For betablockade, the reasons for discontinuation of treatment are not known; maybe it was medically directed in some patients because of bradycardia. There is no information on the proportion of emergent versus scheduled surgery. In the study population, there is a very high prevalence of hypertension (near 90%). Thus, hypertension rather than coronary artery disease may have been the reason for betablockade in many patients. Would this have influenced outcome (all-cause mortality rather than cardiac mortality)? Finally, do we know what continuation of BBs meant: were all the usual doses given over the 48-hour period? The authors acknowledge these limitations. Yet, with the large number of patients their conclusions appear to be valid. The story of betablockade is full of paradoxes: from POISE it is clear that BBs should not be initiated just before surgery unless there are clear indications,4 while Kertai et al1 study confirms that they should not be stopped.1 For many years, BBs were regarded as the best pharmacological agents for the prevention of ischemic perioperative cardiovascular events in patients at risk. They were strongly recommended in guidelines,6,7 and in the United States, their administration to patients presenting for surgery was used as index of quality of care. Indeed, the National Quality Forum states: “Evaluate each patient undergoing elective surgery for risk of an acute ischemic cardiac event during surgery, and provide prophylactic treatment of high-risk patients with betablockers.”8 While there was observational evidence for their efficacy in perioperative cardiac protection, there were at the time only 2 randomized controlled trials9,10 with a total of 312 patients. Both confirmed their efficacy but both were criticized for their methodology. Yet the strong recommendations for initiating betablockade before noncardiac surgery remained.6,7 The POISE trial,4 the largest randomized controlled trial in perioperative medicine at the time, with over 8000 patients, showed that BBs reduced the risk of perioperative myocardial infarction, atrial fibrillation, and nonfatal cardiac arrest but increased all-cause mortality and doubled the risk of disabling stroke. Hypotension, bradycardia, and strokes were the major contributors to an increased all-cause mortality.4 Publication of the results of POISE created considerable controversy.11 New guidelines for perioperative betablockade were published. They differed on both sides of the Atlantic. The North American guideline12 was much more cautious in recommending perioperative BBs than the European guideline.7 However, later guidelines (2014)2,3 differ somewhat less than the previous versions. Initiating BB therapy before noncardiac surgery received a very weak recommendation (IIb B) in the European Society of Cardiology/European Society of Anaesthesiology guideline: “Preoperative initiation of BBs may be considered in patients scheduled for high-risk surgery and who have 2 clinical risk factors or American Society of Anesthesiologists physical status III and in patients who have known ischemic heart disease or myocardial ischemia.”3 Similarly the American College of Cardiology/American Heart Association/American Society of Anesthesiologists guideline states (IIb B recommendations): “in patients with intermediate- or high-risk preoperative tests, it may be reasonable to begin BBs before surgery; similarly in patients with ≥3 revised cardiac risk index (RCRI) factors. Initiating BBs in the perioperative setting as an approach to reduce perioperative risk is of uncertain benefit in those with a long-term indication but no other RCRI risk factors and finally: “it may be reasonable to begin perioperative BBs long enough in advance to assess safety and tolerability, preferably >1 day before surgery.” It also states that BB therapy should not be started on the day of surgery because of the risk of harm (class III B).2 By contrast with initiation of betablockade before noncardiac surgery, both sets of guidelines gave a class I recommendation to continue BB administration throughout the perioperative period.2,3 This recommendation was based on observational evidence in a large number of patients. Over the years, some studies have reported on the risks associated with withholding BBs in surgical patients13 and shown that the practice substantially increased the risk of adverse perioperative cardiac events. This is unsurprising as stopping BB administration results in an increase in heart rate and thus compromises coronary perfusion. The ups and downs of perioperative betablockade therapy are not limited to the perioperative period. Over the past decades, BBs have been demoted from first- to third- or fourth-line treatment for arterial hypertension. In acute myocardial infarction, the intravenous administration of atenolol reduced mortality as seen in International Studies of Infarct Survival.14 In contrast, a larger and more recent study, ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), showed that acute betablockade with metoprolol immediately after myocardial infarction is associated with the risk of heart failure.15 Today, the strongest indication for betablockade is left ventricular failure with reduced ejection fraction; this would have been almost inconceivable 30 years ago as BBs were considered strictly contraindicated in heart failure. Thus, after more than 40 years of research into perioperative betablockade, there are still uncertainties. What is clear is that continuing with long-term betablockade is important, while stopping before

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.