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Is There Any Reason To Withhold β Blockers from High-risk Patients with Coronary Artery Disease during Surgery?

Kertai, Miklos D. M.D.*; Bax, Jeroen J. M.D.†; Klein, Jan M.D.*; Poldermans, Don M.D.*

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IN this issue of the Journal, London et al.1 summarize the physiologic foundations and clinical controversies of perioperative β blockers in patients undergoing noncardiac surgery. The presented data provide solid evidence for their efficacy and support a more widespread use for the reduction of perioperative mortality in patients with known or suspected coronary artery disease (CAD), particularly those with diabetes, left ventricular hypertrophy, and renal insufficiency. However, despite their beneficial effects, oddly enough it seems that some physicians are more afraid of the side effects of β blockers than the harmful effects of myocardial ischemia; β blockers are currently underused in the perioperative setting.
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How often are β blockers underused?
In a recent study, Schmidt et al.2 showed that in 158 patients undergoing major noncardiac surgery, of the 67 who were eligible to receive perioperative β blockers only 25 (37%) received β-blocker therapy. Similar results were shown in a survey of Canadian anesthesiologists. 3 This study revealed that 93% of anesthesiologists agreed that β-blockers were beneficial in patients with known CAD, but only 57% reported β-blocker use in these patients, and only 34% of these regular users continued taking β-blockers beyond the early postoperative period. 3
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What may be the reason for withholding β blockers?
The several potential factors preventing more widespread use of β blockers during the perioperative period include (1) β blockers may not be effective enough in reducing perioperative cardiac events, (2) limited experience with respect to timing and dosing of perioperative β blockers, (3) contraindications to β blockers, and (4) availability of effective alternative cardioprotective treatment strategies. These factors are discussed below.
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1. β blockers are effective in reducing perioperative cardiac events.
A rupture of a coronary atherosclerotic plaque is implicated in about half of perioperative myocardial infarctions, resulting in platelet aggregation and thrombus formation. However, the location of perioperative myocardial infarction is not always related to the location of the culprit coronary lesion. In two separate studies, 4,5 histopathologic analyses of coronary arteries and myocardium revealed that predicting the site of infarction based on severity of underlying stenosis would have been unsuccessful in a majority of the patients. This may indicate the presence of CAD in numerous locations throughout the coronary tree and the possibility that perioperative myocardial infarction may result from plaque rupture and thrombosis at the site of a hemodynamically (in)-significant atherosclerotic plaque. In addition to acute plaque rupture and thrombosis, prolonged myocardial ischemia due to a supply-demand mismatch has been suggested as another mechanism for major cardiac complications. Patients undergoing noncardiac surgery with known CAD or those at risk may have an incidence of perioperative myocardial ischemia exceeding 40% with an associated 9- to 16-fold increased risk for cardiac death and myocardial infarction. 6,7 During prolonged myocardial ischemia, elevated levels of cardiac troponins can be detected verifying structural myocardial damage. Elevated levels of cardiac troponins are confirmed to have prognostic information for perioperative and long-term cardiac complications. 8,9 In a recent study, we demonstrated that asymptomatic perioperative myocardial damage, indicated by cardiac troponin elevations without angina pectoris or new electrocardiographic changes, resulted in a more than 2-fold increase in risk of all-cause mortality during a median follow-up of 4 yr (personal communication, Don Poldermans, M.D., Professor, Department of Vascular Surgery, Erasmus Medical Center, Rotterdam, The Netherlands, August 2003).
This Editorial View accompanies the following article: London MJ, Zaugg M, Schaub MC, Spahn DR. Perioperative β-adrenergic receptor blockade: Physiologic foundations and clinical controversies. Anesthesiology 2004; 100:170–5.
β blockers may play a substantial role in the prevention of perioperative cardiac complications. Apart from their direct hemodynamic effect, such as reduction in heart rate and contractility, β blockers may also indirectly influence the determinants of shear stress and reduce inflammation through decreases in sympathetic tone. 10 Reduction in heart rate and pulse pressure by β blockers are also considered important in stabilizing the vulnerable plaques. As a result of these properties of β blockers, the intensity of myocardial ischemia is reduced and the extent of myocardial infarction can be decreased. Several studies have demonstrated the clinical efficacy of perioperative β-blocker use to decrease cardiac complications in patients with risk factors or those with known CAD who are undergoing noncardiac surgery. Mangano et al.11 randomly assigned 200 patients to receive atenolol or placebo before the induction of anesthesia, immediately after surgery, and daily throughout their hospital stay. There was no difference in the incidence of perioperative myocardial infarction or cardiac-related death. During long-term follow-up, the mortality was 10% in patients who had been previously given atenolol and 21% in the controls. A more recent study of Poldermans et al.12 randomized patients to bisoprolol an average of 30 days preoperatively with dose adjustment to achieve a resting heart rate of 60 beats per minute or less, and patients continued to receive β blockers for an average of 2 yr. The results of these studies, combined with previous investigations, show a protective effect of β blockers for perioperative myocardial ischemia and support the hypothesis that perioperative β-blocker use can substantially reduce cardiac risk among high-risk patients undergoing noncardiac surgery.
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2. Timing, hemodynamic targets, and duration of perioperative β-blocker use.
Currently, there is no consensus about the optimal timing of institution of perioperative β blockers, duration of therapy after surgery, or hemodynamic targets. On the basis of our own experience, treatment with perioperative β blockers should start as soon as the eligibility of a high-risk patient for surgery is confirmed. If possible, this should occur days or weeks before surgery with dose adjustment to achieve a resting heart rate of 60 beats per minute or less. 12 London et al.1 clearly state that provision of perioperative β blockade may allow better assessment of tolerance to therapy and perhaps might take advantage of “cellular-level” effects of β blockade, but these advantages are strictly speculative. Adjusting treatment to resting heart rate alone may not be an adequate measure of β blockade, which could be most accurately assessed by response to exercise or adrenergic challenge. In that respect, in patients at intermediate- or high-risk who are already receiving β blockers, additional noninvasive testing as part of the routine preoperative risk assessment with dobutamine stress echocardiography could be useful in facilitating additional titration of β blockers in relation to the heart rate at which myocardial ischemia is induced. A few studies are available to derive recommendations for the duration of β-blocker use. Mangano et al.11 demonstrated that patients receiving perioperative β blockers experienced fewer cardiac events throughout the 2-year study period than those in the placebo group. Poldermans et al.13 showed that a selective β1 blocker bisoprolol reduced cardiac death and myocardial infarction in high-risk patients for as long as 2 yr after successful major vascular surgery.
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3. Adverse effects of perioperative β blockers.
Contraindications such as the presence of severe left ventricular dysfunction, exacerbation of reactive airway disease, insulin-dependent diabetes, or worsening of symptoms of peripheral vascular disease may be important reasons to withhold β blockers. Despite these “classic” contraindications, several investigators have demonstrated that perioperative and long-term administration of β blockers was well tolerated with no substantial increase of adverse effects, despite that many of these patients were known to have CAD, pulmonary disease, diabetes mellitus, and intermittent claudication. 11–16 The use of cardio-selective β blockers, such as bisoprolol or metoprolol, given their lower potential for adverse effects at routine clinical doses, may further encourage physicians to use these agents in patients with relative contraindication to β blockers. The potential absolute contraindication to β blockers, such as major atrioventricular nodal conduction disease in the absence of a pacemaker, severe asthma, or a strong reactive airway disease, may preclude patients from tolerating β blockers. In such situations, α2 agonists or less invasive anesthetic and surgical techniques should be considered.
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4. Alternative cardioprotective treatment strategies.
Prophylactic coronary revascularization prior to surgery could be an attractive alternative approach for the management of CAD in patients who have been identified as having increased risk for cardiac complications. This may not only improve perioperative outcome, but it would also result in better long-term survival after surgery. No prospective, randomized trials have addressed the effectiveness of coronary bypass grafting (CABG) for reducing the incidence of perioperative cardiac complications. 17,18 The findings of retrospective studies suggest that, when indicated, CABG might reduce the risk of cardiac complications. However, one should consider that the combined risks of CABG and noncardiac surgery might exceed the risk of noncardiac surgery alone. A possible less invasive alternative to preoperative CABG would be percutaneous transluminal coronary angioplasty with coronary stenting, provided that a delay of surgery of at least 6 weeks is acceptable. In two recent studies it was shown that patients treated with percutaneous transluminal coronary angioplasty and coronary stenting were at high risk for perioperative mortality, stent thrombosis, or bleeding complications. 19,20 The frequency of these events was higher among patients undergoing surgery within 6 weeks of stent placement. Until randomized trials become available, it is recommended to follow the American College of Cardiology/American Heart Association guidelines and to perform CABG or percutaneous transluminal coronary angioplasty if they are indicated independently of the need for noncardiac surgery.
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Recently, data have been reported about the cardioprotective effect of lipid-lowering medications, such as hepatic hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) (fig. 1). Poldermans et al.21 demonstrated that statin use was associated with a more than 4-fold reduction of perioperative mortality in patients undergoing vascular surgery.
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Recommendations:
The findings of these studies and the work of London et al.1 reveal that despite that perioperative β blockers have proved beneficial in high-risk patients, they are still underused and enhancing β-blocker use should be a priority. Practice guidelines of the American College of Cardiology/American Heart Association and the American College of Physicians may provide one possible approach for improving the use of perioperative β blockers in patients with known CAD or those at risk who are undergoing major noncardiac surgery. According to these guidelines and previous clinical studies, β blockers should be prescribed to all patients with one or more risk factors correlated with higher risk of cardiac complications. Cardioselective β blockers such as bisoprolol or metoprolol should be started days to weeks before a planned surgical procedure, aiming at a resting heart rate of 60 beats per minute. During surgery, additional intravenous β-blocker therapy can be administrated, whereas after surgery in patients with multiple risk factors for CAD, β blockers should be continued to reduce long-term cardiac complications.
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References

1. London MJ, Zaugg M, Schaub MC, Spahn DR: Perioperative beta-adrenergic receptor blockade: Physiologic foundations and clinical controversies. A nesthesiology 2004; 100: 170–5

2. Schmidt M, Lindenauer PK, Fitzgerald JL, Benjamin EM: Forecasting the impact of a clinical practice guideline for perioperative β-blockers to reduce cardiovascular morbidity and mortality. Arch Intern Med 2002; 162: 63–9

3. VanDenKerkhof EG, Milne B, Parlow JL: Knowledge and practice regarding prophylactic perioperative beta blockade in patients undergoing noncardiac surgery: A survey of Canadian anesthesiologists. Anesth Analg 2003; 96: 1558–65

4. Dawood MM, Gutpa DK, Southern J, Walia A, Atkinson JB, Eagle KA: Pathology of fatal perioperative myocardial infarction: Implications regarding pathophysiology and prevention. Int J Cardiol 1996; 57: 37–44

5. Poldermans D, Boersma E, Bax JJ, Kliffen M, van Urk H, van de Ven L, Roelandt JRTC, Thomson IR: Correlation of location of acute myocardial infarct after noncardiac vascular surgery with preoperative dobutamine echocardiographic findings. Am J Cardiol 2001; 88: 1413–4

6. Mangano DT, Wong MG, London MJ, Tubau JF, Rapp JA: Perioperative myocardial ischemia in patients undergoing noncardiac surgery. II: Incidence and severity during the 1st week after surgery. The Study of Perioperative Ischemia (SPI) Research Group. J Am Coll Cardiol 1991; 17: 851–7

7. Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM: Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. The Study of Perioperative Ischemia Research Group (see comments). N Engl J Med 1990; 323: 1781–8

8. Kim LJ, Martinez EA, Faraday N, Dorman T, Fleisher LA, Perler BA, Williams GM, Chan D, Pronovost PJ: Cardiac troponin I predicts short-term mortality in vascular surgery patients. Circulation 2002; 106: 2366–71

9. Lopez-Jimenez F, Goldman L, Sacks DB, Thomas EJ, Johnson PA, Cook EF, Lee TH: Prognostic value of cardiac troponin T after noncardiac surgery: 6-month follow-up data. J Am Coll Cardiol 1997; 29: 1241–5

10. Ohtsuka T, Hamada M, Hiasa G, Sasaki O, Suzuki M, Hara Y, Shigematsu Y, Hiwada K: Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy. J Am Coll Cardiol 2001; 37: 412–7

11. Mangano DT, Layug EL, Wallace A, Tateo I: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996; 335: 1713–20

12. Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, Baars HF, Yo TI, Trocino G, Vigna C, Roelandt JR, van Urk H: 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: 1789–94

13. Poldermans D, Boersma E, Bax JJ, Thomson IR, Paelinck B, van de Ven LL, Scheffer MG, Trocino G, Vigna C, Baars HF, van Urk H, Roelandt JR: Bisoprolol reduces cardiac death and myocardial infarction in high-risk patients as long as 2 years after successful major vascular surgery. Eur Heart J 2001; 22: 1353–8

14. Wallace A, Layug B, Tateo I, Li J, Hollenberg M, Browner W, Miller D, Mangano DT: Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group. A nesthesiology 1998; 88: 7–17

15. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldmanmd AM, Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, Noble RJ, Packer M, Silver MA, Stevenson LW, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith SC, Jr: ACC/AHA Guidelines for the evaluation and management of chronic heart failure in the Adult: Executive Summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation 2001; 104: 2996–3007

16. Salpeter SR, Ormiston TM, Salpeter EE: Cardioselective beta-blockers in patients with reactive airway disease: A meta-analysis. Ann Intern Med 2002; 137: 715–25

17. Fleisher LA, Eagle KA, Shaffer T, Anderson GF: Perioperative- and long-term mortality rates after major vascular surgery: The relationship to preoperative testing in the medicare population. Anesth Analg 1999; 89: 849–55

18. Eagle KA, Rihal CS, Mickel MC, Holmes DR, Foster ED, Gersh BJ: Cardiac risk of noncardiac surgery: Influence of coronary disease and type of surgery in 3368 operations. CASS Investigators and University of Michigan Heart Care Program. Coronary Artery Surgery Study. Circulation 1997; 96: 1882–7

19. Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE: Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000; 35: 1288–94

20. Wilson SH, Fasseas P, Orford JL, Lennon RJ, Horlocker T, Charnoff NE, Melby S, Berger PB: Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol 2003; 42: 234–40

21. Poldermans D, Bax JJ, Kertai MD, Krenning B, Westerhout CM, Schinkel AFL, Thomson IR, Lansberg PJ, Fleisher LA, Klein J, van Urk H, Roelandt JRTC, Boersma E: Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107: 1848–51

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