Editorial I

Peri-operative ß-blockade: a useful treatment that should be greeted with cautious enthusiasm

S. J. Howell, J. W. Sear and P. Foex

Over the past decade, there have been several reports on the use of peri-operative ß-adrenoceptor blockade to reduce peak heart rates in response to noxious stimuli or to myocardial ischaemia in patients with arterial hypertension or coronary artery disease.1–4 Indeed even our sister journal (the British Journal of Surgery) has recently published a leading article advocating the widespread use of ß-adrenoceptor blockade in all older patients undergoing abdominal surgery, as well as in all patients undergoing vascular surgery.5 But does the available evidence really support such a stance?

It is proposed that the sympatholytic effects of ß-blockade may reduce the incidence of peri-operative cardiac complications. This is certainly plausible. If we believe that peri-operative cardiac events are a result of a supply– demand imbalance in the delivery of oxygen to the myocardium, then any reductions in heart rate and blood pressure produced by ß-blockers may minimize such imbalance. A number of studies have shown that peri-operative ß-adrenergic blockade reduces the incidence of peri-operative myocardial ischaemia. 1 6 7

But peri-operative myocardial infarction may not be a result of supply–demand imbalance, but to acute coronary events precipitated by the rupture of an atheromatous plaque in the coronary circulation leading to the occlusion of a coronary artery by thrombus. Thus, Dawood and colleagues found evidence of acute coronary events in the majority of 42 patients who suffered peri-operative myocardial infarction and subsequently underwent post-mortem.8

It is well established that ß-blockers are effective for the secondary prevention of acute coronary syndromes.9 It is proposed that the haemodynamic changes induced by ß-blockers reduce the shear stress across atheromatous plaques and so reduce the incidence of plaque rupture and consequent acute coronary thrombosis.10 Alternatively, the beneficial effects of ß-blockade may be due to a reduction in the incidence of arrhythmias,11 either or both of these mechanisms may operate in the peri-operative period. Another possible mechanism whereby benefit could accrue from peri-operative ß-adrenergic blockade is a reduction in the neuroendocrine stress response to surgery. However, Zaugg and colleagues were not able to demonstrate such an effect in a population of elderly patients undergoing non-cardiac surgery.12

There is certainly evidence from observational studies and non-randomized trials that peri-operative ß-blockade reduces the occurrence of peri-operative cardiovascular morbidity, as determined by pressor and chronotropic responses as well as ECG changes associated with ischaemia.1 6 13 14 However, these are all surrogate measures of cardiac outcome—what the anaesthetist wants to be shown is that a given treatment reduces hard outcome measures (such as cardiac death; Q and non-Q wave infarction; unstable angina; congestive cardiac failure; lethal arrhythmias; renal failure and cerebrovascular accidents). Such outcomes have been addressed in two recent papers.

Mangano and colleagues examined the benefit of peri-operative ß-adrenergic blockade in a randomized controlled trial.15 They studied patients who either had a history of coronary artery disease or had risk factors for coronary artery disease. Patients were allocated to receive either atenolol or placebo before and for 1 week after surgery. Outcomes following discharge from hospital were studied. The authors reported a reduction in overall mortality and combined cardiovascular mortality in the 2 yr following discharge from hospital.

Their study has been criticized on a number of grounds. Patients who were already receiving ß-blockers had them discontinued on entry to the study and randomized to ß-blocker or placebo. It was felt that this subjected patients who either had or were likely to have coronary artery disease to the hazards of ß-blocker withdrawal. Deaths and adverse events in hospital were ignored in the analysis. While the effect of ß-adrenergic blockade was significant on survival analysis, it appears that this effect was not significant when outcomes were assessed on ‘an intention to treat analysis’ that included both in-hospital and long-term adverse events.

These findings of Mangano and colleagues15 have been further questioned by Leung and Manku.16 They suggest that the decreased survival may be due not to lack of treatment with atenolol but to the high incidence of diabetes mellitus (32%) among the patients studied. Thus, on balance this study presents some evidence for benefit from peri-operative ß-blockade in intermediate and high-risk patients undergoing major surgery, but is by no means conclusive.

A second, more recent study has examined the benefits of peri-operative ß-adrenergic blockade with bisoprolol.17 Patients presenting for vascular surgery who had inducible wall motion abnormalities on dobutamine stress echocardiography were studied. They were randomized to standard care alone or standard care and peri-operative ß-blockade with bisoprolol, which was started prior to admission to hospital and continued for 1 week after surgery. The main outcome measures were death and cardiac events in hospital. A clear benefit from bisoprolol was demonstrated. Non-fatal myocardial infarction occurred in nine patients given standard care only (17%) and in none of those given standard care plus bisoprolol (P<0.001). There were two deaths from cardiac causes in the bisoprolol group (3.4%), as compared with nine in the standard-care group (17%, P=0.02). Hence, there was a clear benefit in this study of peri-operative ß-adrenergic blockade in a high-risk group of patients. The patients studied were known to have inducible myocardial wall motion abnormalities and the overall cardiac event rate in the standard care group was 34%. On the basis of these findings, it would seem reasonable to suggest that patients who have evidence of inducible myocardial ischaemia on preoperative cardiac stress testing should be given a cardio-selective ß-adrenergic blocker in the peri-operative period. Generally, the presence of reversible ischaemia is regarded as an indication for coronary angiography followed, where appropriate, by prophylactic coronary revascularization prior to major surgery. In this study, only a few patients underwent coronary artery bypass surgery; and this may have contributed to a high complication rate in the placebo group.

However in many centres, it would be difficult to identify the subgroup of patients studied by Poldermans and colleagues.17 Most hospitals do not have the resources to include cardiac stress testing in the preparation of patients for major surgery. Where such testing is available, it is often only used routinely in patients who are to undergo surgery of the thoracic or abdominal aorta. When such testing is used, a significant proportion of patients who have an explicit history of cardiac disease will have a negative test. Such patients are very likely to have non-critical plaques in their coronary arteries. Should these patients receive ß-blockers in the peri-operative period, especially in the light of the findings of the post-mortem study of Dawood and colleagues8 that the majority of acute coronary events leading to peri-operative cardiac death are associated with thrombus formation at previously non-critical plaques?

It seems appropriate that patients who are to undergo major surgery and who have evidence of inducible myocardial ischaemia on stress testing should receive ß-adrenergic blockers in the peri-operative period. However, it is not clear that patients presenting for major surgery who have a history of ischaemic heart disease should be given ß-blockers on the basis of this history alone. Mangano and colleagues15 studied patients who either had a history of ischaemic heart disease or who had two or more cardiac risk factors. Thus, many of the patients in their study will have been subject to intermediate rather than high risk of adverse cardiac events. The flaws in their study have already been described and lead one to suggest their study was inconclusive. Although it seems likely that peri-operative ß-adrenergic blockade would be of benefit in intermediate risk patients, the case remains unproven. There is an incidence of peri-operative myocardial infarction in older patients who have no previous history of ischaemic heart disease and who undergo major surgery. If the risks of peri-operative ß-adrenergic blockade are low, there may be a case for giving ß-blockers to all patients over a certain age in whom they are not contra-indicated and who are to undergo elective major surgery. However, there are no data to support this proposition.

In the non-operative setting, ß-blocker therapy for the secondary prevention of myocardial infarction offers the greatest benefit to patients over the age of 60 and patients at a moderate or high risk for reinfarction or cardiac death (for example patients with LV dysfunction or arrhythmias or both).18

More recently, Urban and colleagues have examined the use of post-operative prophylactic ß-blockade in orthopaedic patients at risk of myocardial ischaemia.4 The aim was to control the post-operative heart rate to <80 beats min–1 with an initial infusion of esmolol and then oral metoprolol. Early post-operative ECG changes associated with ischaemia were reduced during the esmolol infusion. Also, for the next two post-operative days there was no effect on the incidences of post-operative cardiac events (angina, congestive cardiac failure, and/or ECG changes and total serum creatine phosphokinase isoenzyme MB fraction index >3.0) or myocardial infarction.

In all of these papers, the benefits (if any) of peri-operative ß-adrenergic blockade have to be quantified and set against any risk of harm. Examining these two key studies more closely, Poldermans and colleagues17 report a RR (relative risk) for cardiac death of 0.20 (95% CI 0.05–0.88) at 30 days post-operation; while Mangano and colleagues15 report a RR of 0.36 (0.13–0.96) at 24 months. The corresponding RR values for combined cardiac deaths and cardiovascular events are 0.10 (0.02–0.41) and 0.51 (0.31–0.85), respectively.

It has become clear that modest doses of ß-blocker may also yield benefit in heart failure. The HOT study indicated that ß-blockers do not lead to a worsening of peripheral vascular disease and, in fact, there was an excess of amputations in the captopril group.19 The medical setting is different to the peri-operative period in that in the latter there are the cardiovascular effects of anaesthesia and of the stress response to surgery to take into account. The currently available studies suggest that the use of ß-blockers in the peri-operative period is not associated with significant risk so long as they are withheld if there is relative bradycardia or hypotension. However, this is based on small studies. In intermediate and low risk patients, a large number of patients may have to be treated to prevent one potential peri-operative myocardial infarction. This may be justified, but only if it is clear that adverse events associated with this strategy are rare.

A particular concern is how long treatment should be continued and the possible adverse effects of stopping ß-blockers. In the study of Mangano and colleagues,15 ß-blockers were continued for 7 days or until discharge from hospital, which ever was the sooner. In that reported by Poldermans,17 ß-blockers were continued for 30 days after surgery. Neither study reported any adverse effects from discontinuing ß-blockade. However, it is suggested that these drugs should be given to patients who either have, or may have, coronary artery disease. It remains possible that larger studies could report the occurrence of angina or myocardial infarction when ß-blockers are withdrawn.

Both randomized controlled trials to date have used cardioselective ß-blockers. This seems appropriate. The main considerations here are when should ß-blockers be started and what degree of ß-blockade is required to provide peri-operative cardiac protection. If the ß-blocker is started several days before surgery, as was done in the study reported by Poldermans and colleagues,17 several half-lives will have elapsed by the start of surgery and it is therefore likely that therapeutic levels will be achieved. However, the duration of preoperative treatment may exceed the duration of the peri-operative period for which cardiac protection is sought. Indeed it is possible that ß-blockers will be given to patients in whom it is subsequently decided that surgery is inappropriate. If treatment is to be started at the time of admission for surgery then a much shorter period will be available for therapeutic levels to be achieved. In these circumstances, it would seem sensible to use an agent with a short half-life such as metoprolol. Whichever drug is chosen, the optimal dose remains uncertain. It is not clear what degree of sympathetic blockade is required to offer cardiac protection.

There is some evidence that other sympatholytic therapies, such as thoracic epidural block and treatment with {alpha}-2 agonists reduce the incidence of peri-operative myocardial ischaemia.20 The question arises of whether these treatments should be used together. May we expect cardiac protection from ß-blockers in a patient who has received a thoracic epidural? Indeed, will the combined sympatholytic effect of the two treatments produce unacceptable hypotension?

While peri-operative ß-blockade may offer a valuable intervention that reduces the incidence of peri-operative cardiac complications, a considerable amount of work is still to be done. Should these drugs only be given to patients at high risk of peri-operative complications, or may they have a place in the management of intermediate and low risk patients undergoing major surgery? Is there an ideal time to initiate ß-blockade and for how long should it be continued? Is peri-operative ß-blockade of value when other sympatholytic therapies are also being used? ß-blockers are useful, but we should not embrace them uncritically.

In contrast to these studies examining the effects of ‘acute’ administration of ß-blocking drugs peri-operatively, our own observational studies in a general surgical population (but including high risk vascular surgical patients) have failed to demonstrate an effect of chronic ß-blockade on either peri-operative silent myocardial ischaemia;21 on cardiac mortality at 30 days;22 or on cardiac mortality or combined cardiac mortality and cardiovascular complications at 1 year post-operation.23 24

Thus, while it is accepted that chronic treatment with ß-blockers should be continued throughout the peri-operative period and is well tolerated, the peri-operative introduction of ß-blockers and the associated side-effects have not been extensively studied. Moreover those studies to date have been carried out in a high dependency or intensive care environment where adverse effects can be easily detected and corrected. This may not be the case on an ordinary ward. The safety of the deliberate addition of ß-blocker shortly before surgery needs to be established.

S. J. Howell

University Department of Anaesthesia

University of Bristol

Bristol, UK

J. W. Sear

P. Foex

Nuffield Department of Anaesthetics

University of Oxford

John Radcliffe Hospital

Headington

Oxford OX3 9DU, UK

References

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