Clinical Resarch Artrcale
 

Perioperative beta-blockers: is it still useful?
W-J Flu, J-P van Kuijk, J.J Bax, D. Poldermans
Department of Anaesthesiology, Erasmus Medical Center, Rotterdam, The Netherlands
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Department of Vascular Surgery, Erasmus Medical Center, Rotterdam, The Netherlands

Introduction

Beta-blockers are established therapeutic agents for patients with hypertension, heart failure and coronary artery disease. There is still considerable debate concerning the protective effect of beta-blocker therapy towards perioperative coronary events, which will be outlined it this review article. The present article provides an overview of leading observational studies, randomized controlled trials, meta-analyses and guidelines assessing perioperative beta-blocker therapy.

Risk stratification in non-cardiac surgery

In the United States, 30 million non-cardiac surgical procedures are performed every year and by 2020 the number of patients eligible for surgery will increase by 25%. The total number of surgical procedures will rise even faster because the frequency of intervention increases dramatically with age. Surgical patients are older and sicker than the general population (27% are older than 65 years versus 11% of the general population) and 40% have atherosclerotic disease risk factors 1. Preoperative risk stratification is of great importance to predict cardiac outcome in patients requiring major non-cardiac surgery. Patients who are at increased risk of postoperative events may benefit from medical treatment or other preoperative interventions. Therefore, identification of these patients is an important goal in preoperative screening strategies. Tools for preoperative screening include resting echocardiography, dobutamine stress echocardiography, biomarkers and cardiac risk scores. Multiple risk indices have been developed over the years 2, 3, however the Lee index (or revised cardiac risk index) is generally considered to be the most widely used index to predict peri-operative cardiac risk 4. In order to optimize the prediction of perioperative mortality in vascular surgery patients, Boersma et al developed a simple risk-index that accounts for significant clinical risk factors and medication use to predict perioperative all-cause mortality. By summing individual scores derived from the given predictors (myocardial infarction, angina pectoris, congestive heart failure, cerebrovascular disease, diabetes mellitus, renal dysfunction and age over 70 years) and with the use of the total risk score, the patient’s probability of perioperative mortality can be estimated 5, 6. Although previous studies emphasize ischemic heart disease as the most important risk factor for perioperative complications, heart failure is known to be as equally important 7.

Cardiac complications in non-cardiac surgery

Cardiac complications are the leading cause of perioperative morbidity and mortality. Mangano et al found an incidence of 2.5% for the composite endpoint of perioperative myocardial infarction or cardiac death in unselected patients over the age of 40 (range: 2.0–3.7%) 8, 9. Importantly, episodes of peri-operative myocardial infarction or ischemia are most often silent and therefore patients remain untreated. This might contribute to an increased risk of long-term cardiovascular mortality 10, 11. Coronary artery disease and heart failure are the major risk factors of adverse postoperative outcome after non-cardiac surgery 4. During surgery, the heart requires a high level of oxygen supply, a process determined by 1) the coronary blood flow and 2) the oxygen carrying capacity of blood. In addition, high catecholamine production is responsible for vasoconstriction and haemodynamic stress 8 leading to an increased oxygen demand intra-operatively. An increase in oxygen demand must be met by an increase in coronary blood flow. When the oxygen supply is insufficient due to coronary artery stenosis, this creates an imbalance between oxygen-supply and demand, which can lead to myocardial ischemia and infarction 12. For this reason, patients with coronary artery stenosis are at increased risk for perioperative myocardial damage due to an oxygen supply–demand mismatch 13. Patients with diastolic heart failure, characterized by concentric remodelling and left ventricular hypertrophy, have a reduced coronary flow reserve making them susceptible to peri-operative myocardial damage 14. Patients with systolic left ventricular dysfunction have a reduced cardiac output due to eccentric remodelling with concomitant left ventricular dilatation. Surgical stress in combination with perioperative fluid administration increases ventricular pre- and afterload, making patients with a systolic left ventricular dysfunction susceptible for perioperative myocardial damage 15. Generally the risk of perioperative complications, such as myocardial ischemia and infarction, is dependent on 1) the condition of the patient, 2) co morbidities, 3) the patients condition prior to surgery and 4) the duration of the surgical procedure.

Correspondence:  Don Poldermans, M.D., Ph.D.Department of Vascular Surgery Erasmus Medical Center, Room H805, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands
E-mail:
[email protected]
Phone: +31 10 7034613
fax: +31 10 7034957

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Beta-blocker therapy in non-cardiac surgery:
Mechanism of action
During surgery, adequate hemodynamic control is achieved through sympathetic tone attenuation due to volatile anaesthetics 8. Furthermore, to reduce postoperative morbidity and mortality adequate perioperative medical therapy plays a pivotal role and should at least contain a beta-blocker in high-risk patients. Beta-blockers are established therapeutic agents for patients with hypertension, heart failure and coronary artery disease. In the non-surgical setting beta-blockers are widely used for the prevention and treatment of ischemic heart disease and heart failure, all major determinants of adverse postoperative outcome. Beta-blockers are known to exert: 1) anti-arrhythmic effects, 2) anti-inflammatory effects, 3) antirenin-angiotensin properties and 4) a shift in energy metabolism 16-18. Surgical procedures are associated with perioperative tachycardia and increased myocardial contractility leading to an increased oxygen demand 13. Beta-blockers have shown to reduce the myocardial oxygen demand by reducing heart rate, systolic pressure and ventricular contractile force. Furthermore, Beta-blockers promote coronary plaque stability by reducing mechanical and shear stresses and their anti-inflammatory properties have a beneficial effect towards coronary plaque stabilization as well 19, 20.

An overview of the literature

There is still considerable debate concerning the protective effect of beta-blocker therapy towards perioperative coronary events and several randomized controlled trials have demonstrated negative results. In 2004, the PeriOperative Beta-BLockadE (POBBLE)  trial included a small number of 103 low-risk patients (patients with a history of ischemic heart disease were excluded from the study) scheduled for major vascular surgery in a period of three years 21. Patients were randomized, to receive either metoprolol 25 mg or 50 mg or placebo, with treatment initiated one day prior to surgery and continued until 7 days postoperatively. In the POBBLE trial the duration of hospitalization was shorter in patients receiving metoprolol versus placebo (10 days versus 12 days). However, no difference was observed in the incidence of perioperative cardiovascular events between the two randomized groups (placebo: 34%, metoprolol 32%; RR 0.87, 95%CI 0.48-1.55). In addition, the POBBLE trial investigators found a very high number of perioperative cardiovascular event over 30%, in low-risk patients, which is remarkable. In 2006. no difference in the occurrence of post-operative cardiovascular events (10.2 and 12% respectively, p=0.057) was observed in the Metoprolol After Vascular Surgery (MAVS) trial 22. In total, 496 patients were treated with 25-100mg

 

metoprolol or placebo twice a day. Treatment started 2 hours prior to surgery and continued until hospital discharge or 5 days after surgery. The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial was published in 2006 and evaluated perioperative treatment with metoprolol (50mg prior to surgery, 100 mg day of surgery and 100mg postoperatively from day 1 to 6) in 921 diabetic patients. They concluded that metoprolol did not significantly reduced 30-day cardiac morbidity and mortality (21% versus 20%; P=0.66) in patients with diabetes 23. Perioperative treatment with Bisoprolol was evaluated in elderly patients undergoing surgery with neuraxial blockade in the Swiss Beta Blocker in Spinal Anesthesia (BBSA) trial 24. In this underpowered study, in which 226 patients were included, bisoprolol did not exert beneficial effects towards cardiovascular outcome, possible due to varying cardiac risk profile of the patients included.

Evidence of beneficial effects of perioperative beta-blocker treatment to reduce perioperative cardiovascular complications is provided by several observational studies 25, 26. 27 28, and more importantly by several randomized controlled trials. A randomized controlled trial conducted by Mangano et al was published in 1996 and included 200 patients with known or suspected coronary artery disease undergoing high-risk non-cardiac surgery 29. Included patients received either atenolol (50mg or 100mg) or placebo before the induction of anaesthesia and immediately after surgery. Atenolol treatment was continued up to 2 years after surgery in most patients and atenolol use was associated with significantly lower mortality rates at 6 months after discharge (0% versus 8%; P=0.005), and after 2 years (10% versus 21%; P=0.019). Beneficial effects of beta-blocker treatment immediately after surgery was demonstrated in 1999 in a study conducted by Raby et al in 1999. They included 26 patients with preoperative ischemia detected by Holter monitoring undergoing major vascular surgery, randomized to receive esmolol (100-300 μg◦kg-1◦min-1 intravenously for 48 hours after surgery) or placebo postoperatively 30. This study was the first to demonstrate that strict heart rate control after surgery, to 20% below the ischemic threshold, markedly reduced the occurrence of postoperative ischemia (placeco: 73% versus esmolol 33%, p<0.05).

DECREASE-I and POISE trial
In 1999, the Poldermans group published the first Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE-I) trial. Primary objective was to evaluate the effect of perioperative bisoprolol treatment on occurrence of nonfatal myocardial infarction and cardiac death within 30 days after major vascular surgery 31. In total 112 cardiac high-risk patients with evidence of myocardial ischemia during preoperative dobutamine stress-echocardiography were included. Around half the patients received bisoprolol (2.5-10mg) carefully titrated to obtain a perioperative heart rate between 60-65 beats per minute.

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Treatment was started at an average of 37 days prior to surgery and treatment continued at least 30 days after treatment. In patients treated with bisoprolol a reduction in the incidence of perioperative cardiovascular death and myocardial infarction from 34% to 3.4% (P<0.001), was demonstrated 31 compared to placebo. Although these results were promising, the PeriOperative ISchemic Evaluation (POISE) trial, published in 2008, caused great discussion regarding side-effects caused by perioperative treatment with beta-blokcers. The POISE trial included 8351 patients either to receive placebo or treatment with metoprolol succinate using the following treatment protocol: 1) 100mg was given 2-4 hours prior to surgery 2) another 100mg within 6 hours and followed by 3) another 200mg 12-18 hours post surgery if permitted by heart rate and blood pressure. The primary endpoint (cardiac death, myocardial infarction or cardiac arrest) was reduced in the metoprolol group, compared with placebo (5.8% vs. 6.9%, hazard ratio 0.83, 95% CI 0.70-0.99, p=0.04). However, the 30% decrease of non-fatal myocardial infarction (3.6 versus 5.1%, p=0.0008) was accompanied by a 33% increase in total mortality (3.1% versus 2.3%, p=0.03) and a twofold increase risk in stroke (1.0 versus 0.5%, p=0.005) 32. The above mentioned randomized controlled trial are summarized in Table 1.

 

Putting the literature in perspective
The most important clinical trials to evaluate the effect of perioperative beta-blocker treatment have brought forward conflicting results regarding its efficacy.  Treatment with bisoprolol was associated with better results compared to metoprolol or atenolol. The type of beta-blocker used, therefore, might influence the effectiveness of beta-blocker therapy. In comparison with other beta 1-adrenoceptor antagonists (e.g. atenolol, metoprolol), bisoprolol proved to be the compound with the highest beta-1 selectivity in all in vitro and in vivo experiments and in all animal species investigated 33-36. Negative inotropic and chonotropic effects derived from highly selective beta-1 blockade might exert most beneficial perioperative effects towards cardiovascular outcome. Another important factor might give an explanation for these conflicting results may be the variation in treatment protocols of the conducted studies. We have discussed four randomized trials in which the beneficial effect of perioperative beta-blocker use was not shown (POBBLE, MAVS, DIPOM and BBSA). In these trial, beta-blocker treatment was started one day prior to surgery or at the day of surgery. In comparison, in the DECREASE-I trial the mean time between initiation of beta-blocker treatment and surgery was 37 days and in the DECREASE-I trial the largest effect of perioperative beta-blocker treatment was demonstrated 31. In addition, the administrated dosage of beta-blocker were different in the above mentioned randomized studies. For instance, in the DECREASE-I trial, vascular surgery patients were treated with low-dose bisoprolol, between 5-10mg once daily. The incidence of stroke in the DECREASE-1 trials was 0,4%, comparable with placebo, while maintaining a significant reduction in cardiac death and nonfatal myocardial infarction from 34% in the standard-care group to 3,4% in the bisoprolol treated group in the first DECREASE-1 trial 31, 37. In comparison, treatment protocol of the POISE trial showed that metoprolol succinate could have been administered on the first day of surgery at a dose up to 400 mg on the day of surgery which resembles the maximum daily therapeutic dose. However, in heart failure patients much lower starting doses are recommended. In patients with NYHA Class II heart failure 12.5 to 25 mg daily is started for two weeks and for hypertension the initial dose is 25 to 100 mg, usually increased at weekly intervals. 

As indicated by the randomized controlled trials conducted by Mangano et al and Raby et al and further demonstrated in the Decrease-I trial, tight heart rate control will maximize the benefit a patients derives from beta-blocker treatment. However, one should avoid to over treat the patient. The most important side effects, which are to be expected with beta-blocker treatment, are bradycardia and hypotension, which usually occur dose-dependently. As already mentioned, the POISE-trial showed that metoprolol succinate treatment  did lower the incidence of myocardial infarction by more than a quarter (5.7% to 4.2%).  However this benefit was outweighed by an increased incidence of stroke and death 32. Post-hoc analyzing demonstrated that stroke was associated with perioperative bradycardia, hypotension, and bleeding complications. Post-hoc analysis also showed that hypotension had the largest population-attributable risk for death and stroke. Importantly, hypotension could be related to the use of a high dose of metoprolol without dose titration in the POISE-trial. Therefore, analysing the safety and tolerability of beta-blockers is as important as assessing the beneficial effects of beta-blockers regarding efficacy. Titration according to tolerance is of utmost importance to obtain tight heart rate control and prevent adverse side effects such as hypotension and bradycardia. The value of adequate heart rate control in improving cardiovascular outcome is not only confirmed in a recent large meta-analysis 38, the latest 2007 ACC/AA guidelines on perioperative care strongly recommend achieving a heart rate between 65-70 beats per minute 39.

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In 2001 Shammash et al evaluated the influence of perioperative beta-blocker withdrawal towards postoperative mortality of vascular surgical patients. They have suggested that discontinuation of beta-blocker therapy immediately after surgery might  increase the risk of postoperative cardiovascular mortality 40. This notion is supported by a study conducted by Hoeks et al, published in 2007, who found that withdrawal of beta-blockers early after surgery is associated with a higher one-year mortality compared to continuous beta-blocker therapy. This study has highlighted the importance of continue beta-blocker therapy in the perioperative period 41. Therefore, the duration of beta-blocker therapy might be a factor of influence on the mixed results provided by the randomized trial which are discussed in this review article. In the DECREASE-I trial patients were treated at least 30 day after surgery and in the study conducted by Mangano et al most patients received atenolol treatment up to two years after surgery.  Atenolol treatment showed to reduce mortality and the occurrence of cardiovascular events up to two years after surgery 29. Perioperative beta-blocker withdrawal might result in a “rebound” effect causing an increase of arterial blood pressure, heart rate and plasma noradrenalin concentrations 42. Esmolol is an ultra-short-acting cardioselective, beta-adrenergic blocking agent with a rapid onset of around 60 seconds and short duration of action between 10 to 20 minutes 43-45. Intra-operative infusion with esmolol might be effective to prevent intra-operative tachycardia and reduce intra-operative left ventricular contractile force. The short acting character of esmolol and continuous hemodynamic monitoring during surgery can limit adverse side effects, such as hypotension or bradycardia. In addition, the long-term beneficial effects of beta-blocker therapy might be explained by a decrease of progress of coronary atherosclerosis 46. In contrast to the instant effect on heart rate control, the effect of beta-blockers on plaque stabilization may therefore be achieved only after prolonged treatment.

Non-cardiac surgery: with or without beta-blockers?

The main question remains if patients undergoing non-cardiac surgery should receive standard beta-blocker treatment. In order to answer this question, addressing the cardiac risk profile of the patients is of major importance, especially since it had been suggested that the absolute risk reduction associated with beta-blocker treatment is most pronounced in patients who are at high-risk for coronary events 47. The MAVS and DIPOM trial did not show evident beneficial effect of beta-blocker treatment, however they included patients at low risks for cardiac complications, whereas the

 

DECREASE-I trial included high-risk cardiac patients. In 2008, a meta-analysis was published in the Lancet addressing the effects of perioperative beta-blocker treatment in more than 12.000 patients. The main result was that beta-blocker treatment resulted in 16 fewer non-fatal myocardial infarctions per 1000 patients, but at the expense of three non-fatal disabling strokes and possibly three fatal cardiac or non-cardiac complications 48. However, around two third of the patients were derived from the POISE trial, and as the author acknowledge, these patients had the greatest weight for the results. A comment Boersma and Poldermans was published in the same edition of the Lancet, in which they conclude that the general mechanism that might explain the excess cerebral complications is unknown and additional hemodynamic data are needed. They address that these hemodynamic data will be the key for updates of treatment guidelines 49. Multiple studies have provided evidence that there is an under-use of beta-blockers in surgery patient 1) even when patients are considered to be at high-risk for cardiovascular events, 2) despite an increase in beta-blocker prescription worldwide 41, 50 and the 3) despite the fact that the ACC/AHA 2006 guidelines (update on perioperative cardiovascular evaluation for noncardiac surgery: focused update on perioperative beta-blocker therapy) 51 advocate perioperative beta-blocker use.

Conclusions
We conclude that long acting beta-blockers, such as bisoprolol, seem to be the agent of preference to reduce adverse perioperative events and enhance postoperative survival. Low dose treatment, initiated al least a month prior to surgery, and up-titration according to tolerance and obtain heart rates between 65 and 70 beats per minute could demonstrate maximal protection without over treating the patients. Furthermore, prolonged treatment after surgery is favoured to maximize the anti-inflammatory properties of beta-blocker therapy with beneficial effects on coronary plaque stabilization. Intra-operatively, the ultra short beta-blocker esmolol, administered via a continuous infusion, could be considered as well to maximally prevent the occurrence of adverse myocardial events. A randomized controlled trial, addressing pre- and postoperative treatment with low-dose bisoprolol and intra-operative treatment with esmolol could demonstrate a maximal protective effect derived from beta-blocker treatment. Patients with at least two revised cardiac risk factors (ischemic heart disease,  congestive heart failure, cerebrovascular disease,  diabetes mellitus, renal dysfunction, age over 70 years and high-risk surgery) should be included to assess maximal risk reduction and provide us with the final answer to the question: “perioperative beta-blockers: is it still useful”.

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