Beta-blockade and other perioperative pharmacological protectors: what is now available and efficacious?

Publication, in 2008, of the results of POISE, the largest randomized controlled trial (RCT) of perioperative beta-blockade, confirmed previous studies that had shown beta-blockade to offer cardiac protection in patients with, or at risk for, coronary heart disease.1Devereaux PJ Yang H Yusuf S et al.Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial.Lancet. 2008; 371: 1839-1847Abstract Full Text Full Text PDF PubMed Scopus (1712) Google Scholar However, this protection was associated with significantly increased all-cause mortality, particularly in patients who became septic or hypotensive, and significantly increased disabling strokes, contributed to by hypotension. Indeed, as might be expected, hypotension and bradycardia were much more frequent in the beta-blocked patients than in the placebo group. There was also controversy surrounding the dose of the slow-release metoprolol preparation used in the trial. It was regarded by some as too high; also the initiation of beta-blockade the day of surgery precluded titration.2Poldermans D Devereaux PJ The experts debate: perioperative beta-blockade for noncardiac surgery-proven safe or not?.Clev Clin J Med. 2009; 76: S84-S92Crossref PubMed Scopus (28) Google Scholar A meta-analysis of RCTs including POISE data showed that some subgroups of patients could benefit from perioperative beta-blockade: those at high risk and those in whom beta-blockade was strictly titrated.3Angeli F Verdecchia P Karthikeyan G Mazzotta G Gentile G Reboldi G Beta-Blockers Reduce Mortality in Patients Undergoing High-Risk Non-Cardiac Surgery.Am J Cardiovasc Drugs. 2010; 10: 247-259Crossref PubMed Scopus (36) Google Scholar However some of the RCTs that were most supportive of beta-blockade4Poldermans D Boersma E Bax JJ et al.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: 1789-1794Crossref PubMed Scopus (1364) Google Scholar, 5Dunkelgrun M Boersma E Schouten O et al.Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: a randomized controlled trial (DECREASE-IV).Ann Surg. 2009; 249: 921-926Crossref PubMed Scopus (256) Google Scholar arise from researches reported by the group led by Professor Poldermans. As Professor Poldermans was dismissed by Erasmus Medical Centre for academic misconduct in 2011, these trials are now regarded as ‘insecure’.6Bouri S Shun-Shin MJ Cole GD Mayet J Francis DP Meta-analysis of secure randomised controlled trials of beta-blockade to prevent perioperative death in non-cardiac surgery.Heart. 2014; 100: 456-464Crossref PubMed Scopus (199) Google Scholar Thus the case for initiating beta-blockade before surgery was weakened. From the position advocated by previous guidelines, where there was support for the initiation of beta-blockade in ALL patients at risk for, or with, coronary disease,7Palda VA Detsky AS Perioperative assessment and management of risk from coronary artery disease.Ann Intern Med. 1997; 127: 313-328Crossref PubMed Scopus (193) Google Scholar the 2009 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines recommended their introduction in patients at high risk,8Fleisher LA Beckman JA Brown KA et al.2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American college of cardiology foundation/American heart association task force on practice guidelines.Circulation. 2009; 120: e169-e276Crossref PubMed Scopus (307) Google Scholar while the European Society of Cardiology (ESC) guideline recommended them also in patients at more moderate risk (ESC).9Poldermans D Bax JJ Boersma E et al.Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery: the Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA).Eur Heart J. 2009; 30: 2769-2812Crossref PubMed Scopus (715) Google Scholar After highly critical comments in respect of the 2009 guidelines in the discussion of a meta-analysis that excluded the ‘insecure’ trials,6Bouri S Shun-Shin MJ Cole GD Mayet J Francis DP Meta-analysis of secure randomised controlled trials of beta-blockade to prevent perioperative death in non-cardiac surgery.Heart. 2014; 100: 456-464Crossref PubMed Scopus (199) Google Scholar the ACCF/AHA and ESC published a joint interim statement in 2013 to the effect that beta-blockade should not be initiated routinely but only after careful evaluation of risks and benefits in individual patients.10ACCF/AHA, ESC Joint Statement: issued by the American College of Cardiology, American Heart Association and the European Society of Cardiology.Available from www.escardio.org.about/press/press-releases/pr-13/Pages/joint-statement-perioperative-guidelines.aspxDate: 2013Google Scholar Updated guidelines from the ACC/AHA11Fleisher LA Fleischmann KE Auerbach AD et al.2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2014; 64: e77-e137Crossref PubMed Scopus (897) Google Scholar and ESC/ESA,12Kristensen SD Knuuti J Saraste A et al.2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA).Eur Heart J. 2014; 35: 2383-2431Crossref PubMed Scopus (145) Google Scholar published in August 2014 now clarify the issue of perioperative beta-blockade (Table 1). Both sets of guidelines recommend to maintain long-term treatment with beta-blockers (recommendation Class I, level of evidence B). As far as initiation of perioperative beta-blockade, there are no Class I, or Class IIa recommendations. There are only relatively weak class IIb recommendations. Essentially the new guidelines recommend to consider starting beta-lockers in patients with known ischaemic heart disease or myocardial ischaemia, and in patients with multiple cardiac risk factors, two in the ESC/ESA guideline, and three in the ACC/AHA guideline. The ACC/AHA guideline suggests that initiating beta-blockers in patients with a compelling indication for beta-blockers but with NO OTHER cardiac risk factor is of uncertain benefit. Both sets of guidelines recommend starting beta-blocker therapy well in advance of surgery, preferably more than one day before surgery (ACC/AHA) or between 30 and 2 days before surgery (ESC/ESA). The possibility of harm is emphasized. The ACC/AHA guideline considers starting beta-blockers the day of surgery as potentially harmful (recommendation III B), a view endorsed by the ESC/ESA guideline with another caveat against initiation of beta-blockers in patients undergoing low-risk surgery (recommendation III B). Interestingly, the ESC/ESA guideline recommends to use atenolol or bisoprolol as first choice (recommendation IIb B). While the 2009 sets of guidelines indicated targets for heart rate, only the ESC/ESA 2014 guideline comments on the need to titrate to resting heart rate 60–70 beats min -1 and systolic blood pressure >100 mm Hg. The ACC/AHA view is that there insufficient evidence in respect of titration.Table 1Comparison of recommendations made by ACCF/AHA (2009) and current ACC/AHA guidelines (2014)2009 ACCF/AHA guideline Recommendations2014 ACC/AHA guideline RecommendationsClass IBeta blockers should be continued in patients undergoing surgery who are receiving beta-blockers for treatment of conditions with ACCF/AHA Class I guideline indications for the drugs I CClass IBeta blockers should be continued in patients undergoing surgery who have been on beta blockers chronically I BClass IIaBeta blockers titrated to heart rate and blood pressure are probably recommended for patients undergoing vascular surgery who are at high cardiac risk owing to coronary artery disease or the finding of cardiac ischaemia on preoperative testing IIa BClass IIaIt is reasonable for the management of beta blockers after surgery to be guided by clinical circumstances, independent of when the agent was started IIa BBeta blockers titrated to heart rate and blood pressure are reasonable for patients in whom preoperative assessment for vascular surgery identifies high cardiac risk, as defined by the presence of more than 1 clinical risk factor IIa CClass IIbIn patients with intermediate- or high-risk myocardial ischaemia noted in preoperative risk stratification tests, it may be reasonable to begin perioperative beta blockers IIb CBeta blockers titrated to heart rate and blood pressure are reasonable for patients in whom preoperative assessment identifies coronary artery disease or high cardiac risk, as defined by the presence of more than 1 clinical risk factor, who are undergoing intermediate-risk surgery IIa BIn patients with 3 or more RCRI risk factors (e.g. diabetes mellitus, HF, CAD, renal insufficiency, cerebrovascular accident), it may be reasonable to begin beta blockers before surgery IIb BClass IIbThe usefulness of beta blockers is uncertain for patients who are undergoing either intermediate risk procedures or vascular surgery in whom preoperative assessment identifies a single clinical risk factor in the absence of coronary artery disease IIb CIn patients with a compelling long-term indication for beta-blocker therapy but no other RCRI risk factors, initiating beta blockers in the perioperative setting as an approach to reduce perioperative risk is of uncertain benefit IIb BThe usefulness of beta blockers is uncertain in patients undergoing vascular surgery with no clinical risk factors* who are not currently taking beta blockers IIb BIn patients in whom beta-blocker therapy is initiated, it may be reasonable to begin perioperative beta blockers long enough in advance to assess safety and tolerability, preferably more than 1 day before surgery IIb BClass IIIBeta blockers should not be given to patients undergoing surgery who have absolute contraindications to beta-blockade III BClass IIIBeta-blocker therapy should not be started on the day of surgery III BRoutine administration of high-dose beta- blockers in the absence of dose titration is not useful and may be harmful to patients not currently taking beta blockers who are undergoing noncardiac surgery III B Open table in a new tab Although the use of RCTs represent the ‘gold standard’ for the development of guidelines, examination of outcomes in observational studies may also be helpful. This is the case with the recent meta-analysis from Wan and colleagues13Wan YD Zhang SG Sun TW Kan QC Wang LX The effects of perioperative beta-blockers on mortality in patients undergoing non-cardiac surgery in real world: A meta-analysis of cohort studies.Int J Cardiol. 2014; 176: 605-610Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Depending upon the individual outcomes considered, the number of patients included was between 52 300 and 470 000. While perioperative beta-blockade was not associated with increased mortality (RR 0.88 [CI 0.75–1.04]), 3 studies with 4101 patients showed that mortality was increased in patients taking beta-blocker on the day of surgery (RR 1.91 [CI 1.01–3.62]). The messages of observational studies are very similar to those of ‘secure’ RCTs; however at variance with RCTs, there was no reduction in the risk of myocardial infarction (107 974 patients, RR 1.3 [0.76–2.23]). Similarly there was only a non-significant increase in the risk of stroke (106 320 patients, RR 1.17 [CI 0.53–2.57]). Thus, for beta-blockade, results from observational studies do not suggest that the current guidelines, urging caution, are not partly representative of ‘real life’. As sympathetic over-activity is detrimental to patients with coronary artery disease, an alternative to beta-adrenoceptor blockade could be the perioperative use of an alpha2-adrenoceptor agonist. Previous RCTs had shown beneficial effects of alpha2- adrenoceptor agonists (mivazerol, dexmetedomidine, clonidine) in cardiac and in non-cardiac surgery;14Oliver MF Goldman L Julian DG Holme I Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT).Anesthesiology. 1999; 91: 951-961Crossref PubMed Scopus (182) Google Scholar, 15Ji F Li Z Nguyen H Young N et al.Perioperative dexmedetomidine improves outcomes of cardiac surgery.Circulation. 2013; 127: 1576-1584Crossref PubMed Scopus (211) Google Scholar, 16Ji F Li Z Young N Moore P Liu H Perioperative dexmedetomidine improves mortality in patients undergoing coronary artery bypass surgery.J Cardiothorac Vasc Anesth. 2014; 28: 267-273Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar while a meta-analysis including all RCTs using clonidine, dexmetedomidine and mivazerol showed significant reductions of major cardiac events in cardiac and non-cardiac surgery.17Wijeysundera DN Naik JS Beattie WS Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis.Am J Med. 2003; 114: 742-752Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar Thus clonidine could be expected to confer protection, even though the number of patients in clonidine RCTs was small. POISE 2 was designed as a 2×2 RCT with clonidine and aspirin and appropriate placebos.18Devereaux PJ Sessler DI Leslie K et al.Clonidine in patients undergoing noncardiac surgery.New Engl J Med. 2014; 370: 1504-1513Crossref PubMed Scopus (213) Google Scholar, 19Devereaux PJ Mrkobrada M Sessler DI et al.Aspirin in patients undergoing noncardiac surgery.New Engl J Med. 2014; 370: 1494-1503Crossref PubMed Scopus (582) Google Scholar The study enrolled just over 10000 patients. Clonidine did not reduce the risk of perioperative cardiac events. Though the dose was low (2 mg orally just before surgery and a 2 mg patch left for three days [or removed in case of hypotension]) it caused clinically important hypotension and bradycardia in a large proportion of patients.16Ji F Li Z Young N Moore P Liu H Perioperative dexmedetomidine improves mortality in patients undergoing coronary artery bypass surgery.J Cardiothorac Vasc Anesth. 2014; 28: 267-273Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar However, at variance with POISE, the clonidine-induced hypotension did not increase all-cause deaths or the risk of stroke. Thus, after the much more cautious recommendations for beta-blockers, an attractive alternative, low-dose clonidine, is clearly not conferring cardiac protection. There was even a significant increase in non-fatal cardiac arrest, and, though not reaching statistical significance, small increases in death from vascular causes, myocardial infarctions, and need for cardiac revascularisation. The 2014 ACC/AHA guidelines are quite clear that alpha2-receptor agonists for the prevention of cardiac events are not recommended (recommendation III B). The ESC/ESA make no specific recommendation but states: therefore, alpha2-receptor agonists should not be administered to patients undergoing non-cardiac surgery, an equivalent to a Class III recommendation. Based also on limited evidence, another candidate for perioperative protection is aspirin. It has been shown to confer protection after cardiac surgery,20Mangano DT for the Multicenter Study of Perioperative Ischemia Research Group Aspirin and mortality from coronary bypass surgery.New Engl J Med. 2002; 347: 1309-1317Crossref PubMed Scopus (563) Google Scholar and its continuation appears to be beneficial in non-cardiac surgery.21Oscarsson A Gupta A Fredrikson M et al.To continue or discontinue aspirin in the perioperative period: a randomized, controlled clinical trial.Br J Anaesth. 2010; 104: 305-312Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar It is generally accepted that aspirin should not be discontinued before surgery22Gerstein NS Schulman PM Gerstein WH Petersen TR Tawil I Should more patients continue aspirin therapy perioperatively?: clinical impact of aspirin withdrawal syndrome.Ann Surg. 2012; 255: 811-819Crossref PubMed Scopus (132) Google Scholar as this increases the risk of adverse cardiac events. Of course there is risk of increased bleeding but this is not usually life-threatening. POISE2 randomly allocated patients to aspirin whether or not they were previously on aspirin, thus in some patients aspirin was withdrawn after randomisation if they were to receive the aspirin-placebo medication. The results of the aspirin arm of the trial showed no cardiac protection and confirmed the risk of increased major bleeding.17Wijeysundera DN Naik JS Beattie WS Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: a meta-analysis.Am J Med. 2003; 114: 742-752Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar Thus another potential candidate for perioperative cardiac protection was found to be ineffective and with significant risks. Unsurprisingly, the ACC/AHA guideline states that initiation or continuation of aspirin is not beneficial in patients undergoing elective non-cardiac, non-carotid, surgery who have not had previous coronary stenting, unless the risk of ischaemic events outweighs the risk of surgical bleeding (recommendation III C). The ESC/ESA guideline states that continuation of aspirin, in patients previously thus treated, may be considered in the perioperative period, and should be based on an individual decision that depends on the perioperative bleeding risk, weighed against the risk of thrombotic complications (recommendation IIb B). Thus, with aspirin, the decision about initiating or continuing its administration needs to be informed by the risk of thrombotic events and the risk of excessive bleeding. Why are there discrepancies between previous RCTs that indicated benefits of alpha2-agonists and aspirin and the results of POISE2, and, maybe also, of POISE in respect of beta-blockade? One possible explanation is the change of ‘context’. Many of the studies that showed benefits of pharmacological interventions recruited patients up to 20 years ago or more. Over the past two decades many aspects of perioperative management have changed and also the management of co-morbidities. Arterial hypertension is controlled much more effectively than 20 or even 10 years ago. Over the past five years, the treatment of acute coronary syndromes has been revolutionised by primary percutaneous interventions. Anaesthetic techniques have changed and perioperative monitoring is now much more comprehensive. These changes over time have contributed to the safety of anaesthesia. Thus, current advances in perioperative medicine may reduce the scope for perioperative pharmacological protection, such that previously effective treatments are no longer beneficial. It also likely that in large RCTs, risks that were present in much smaller trials but never reached statistical significance were ignored, as the small studies were not powered for relatively rare events. By relying too much on the lack of statistical significance, and ignoring trends, we may have allowed serious complications to be disregarded, imperilling our patients. Today only statins have been shown consistently to afford cardiac protection but almost exclusively in observational studies, some very large.23Lindenauer PK Pekow P Wang K Gutierrez B Benjamin EM Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery.J Am Med Assoc. 2004; 291: 2092-2099Crossref PubMed Scopus (370) Google Scholar Initiating statin treatment before surgery has been studied in RCTs in cardiac and non-cardiac surgery. A meta-analysis of these trials has shown that statins reduce the risk of myocardial infarction and atrial fibrillation.24Chopra V Wesorick DH Sussman JB et al.Effect of perioperative statins on death, myocardial infarction, atrial fibrillation, and length of stay: a systematic review and meta-analysis.Arch Surg. 2012; 147: 181-189Crossref PubMed Scopus (93) Google Scholar In non-cardiac surgery the largest studies are those from Professor Poldermans’ group5Dunkelgrun M Boersma E Schouten O et al.Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: a randomized controlled trial (DECREASE-IV).Ann Surg. 2009; 249: 921-926Crossref PubMed Scopus (256) Google Scholar, 25Schouten O Boersma E Hoeks SE et al.Fluvastatin and perioperative events in patients undergoing vascular surgery.N Engl J Med. 2009; 361: 980-989Crossref PubMed Scopus (320) Google Scholar if they are considered ‘insecure’, the number of patients in statins RCTs is reduced from 1186 to 156 and firm conclusions cannot be drawn. However, the evidence from observational studies showing protection in patients on long-term statin medication, suggests that initiating statins ahead of surgery could be beneficial.23Lindenauer PK Pekow P Wang K Gutierrez B Benjamin EM Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery.J Am Med Assoc. 2004; 291: 2092-2099Crossref PubMed Scopus (370) Google Scholar Indeed, there are limited recommendations for the initiation of statins before surgery in the 2009 ACCF/AHA8Fleisher LA Beckman JA Brown KA et al.2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American college of cardiology foundation/American heart association task force on practice guidelines.Circulation. 2009; 120: e169-e276Crossref PubMed Scopus (307) Google Scholar and in the ESC guidelines.9Poldermans D Bax JJ Boersma E et al.Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery: the Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA).Eur Heart J. 2009; 30: 2769-2812Crossref PubMed Scopus (715) Google Scholar While an increasing number of patients at risk for cardiovascular disease take statins, only 32% of patients recruited into POISE1Devereaux PJ Yang H Yusuf S et al.Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial.Lancet. 2008; 371: 1839-1847Abstract Full Text Full Text PDF PubMed Scopus (1712) Google Scholar and 37% into POISE226Devereaux PJ Chan MT Alonso-Coello P et al.Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery.J Am Med Assoc. 2012; 307: 2295-2304Crossref PubMed Scopus (717) Google Scholar were receiving statins at the time of surgery. Thus there may be scope for improving protection by introducing statins preoperatively in patients at risk who should be on statins for medical reasons alone. The new ACC/AHA guidelines recommend to continue statins perioperatively(recommendation I B), with the interesting comment in the ESA/ESC guidelines that continuation of statins should favour statins with long half-life or extended-release (recommendation I C). This is in order to maintain some of statins’ effects at a time oral administration may be impossible. In both guidelines, perioperative initiation of statins is recommended in patients undergoing vascular surgery (IIa B). The ACC/AHA suggests that statins may be considered in patients who have a medical indication and undergo elevated-risk surgery. What then can be done to protect the heart? First of all, it is recommended to maintain chronic beta-blocker and statin therapy. It is also probably reasonable to continue low dose aspirin therapy, unless surgery is associated with a significant risk of excessive bleeding. In selected high-risk patients undergoing high risk surgery beta-blockade initiated as early as possible (at the very least a week before surgery) should be considered for individual patients. Initiating statin therapy in patients who should be on statins for medical reasons alone is also indicated before major surgery. However, initiating clonidine or aspirin for cardiac protection is not supported by evidence. Against the background of the lack of efficacy of pharmacological prophylaxis, maybe a change of strategy is called for. Myocardial injury after non-cardiac surgery (MINS) is associated with significant short- and long-term morbidity and mortality.18Devereaux PJ Sessler DI Leslie K et al.Clonidine in patients undergoing noncardiac surgery.New Engl J Med. 2014; 370: 1504-1513Crossref PubMed Scopus (213) Google Scholar, 27Botto F Alonso-Coello P Chan MT et al.Myocardial Injury after Noncardiac Surgery: A Large, International, Prospective Cohort Study Establishing Diagnostic Criteria, Characteristics, Predictors, and 30-day Outcomes.Anesthesiology. 2014; 120: 564-578Crossref PubMed Scopus (592) Google Scholar Currently there is no agreement on the best way of managing patients with raised troponin concentrations after non-cardiac surgery. Many drugs are used in the management of perioperative ischaemic cardiac events. Beta-blockers, anticoagulants, antiplatelet agents, non-dihydropyridine calcium channel blockers, and statins have all been used, but for most interventions, strong scientific evidence is still lacking. However the reduced risk of adverse outcome in patients with MINS who received aspirin or statins,28Devereaux PJ Xavier D Pogue J et al.Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study.Ann Intern Med. 2011; 154: 523-528Crossref PubMed Scopus (486) Google Scholar suggests that more prospective studies of interventions could are needed and may prove very valuable.