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  • 1. Beta-Blockers and Reduction of Cardiac Events in Noncardiac Surgery Christine Dehlendorf, MD Journal Club November 13, 2002
  • 2. Context
    • 30 million patients per year have non-cardiac surgery, and 3 million of these have or are at risk for having cardiovascular disease
    • Concern for cardiovascular disease the most common reason for pre-operative consultation
    • Consultations often limited to:
      • Estimation of risk
      • Postponing or canceling surgery
      • Consideration of revascularization
  • 3. Managing the Risk – The rationale for using beta-blockers peri-operatively
    • Studies have found post-operative ischemia to increase subsequent myocardial events up to 28 fold.
    • Post-operative ischemia estimated to occur in 25-50% of at risk patients.
    • May be related to elevated heart rate found post-operatively.
  • 4. Relevance to the Family Physician
    • Important role in pre-operative evaluations
    • Managing pre and post-operative inpatients
  • 5. Beta-Blockers and Reduction of Cardiac Events in Noncardiac Surgery AD Auerbach and L Goldman. JAMA 2002;287:1435-1444.
    • Scientific review of RCT data on peri-operative beta blocker use.
    • Five studies from 1988 to 2000.
    • Total of less than 600 patients.
    • Very heterogenous data sources.
  • 6. Review of Studies Until discharge from hospital To termination of anesthesia 48 hours 30 days 2 years Length of Follow-up Myocardial ischemia and infarction Esmolol after surgery, then changed to metoprolol 129, with or at risk for cardiac disease Urban, 2000 Myocardial ischemia Atenolol, labetalol or oxprenolol, one oral dose before anesthesia 128, untreated hypertensives Stone, 1988 Myocardial ischemia Esmolol, after surgery for 48 hours 26, pre-op ischemia by Holter Raby, 1999 Cardiac death and non-fatal MI Bisoprolol, 37 days before and 30 days after surgery 112, positive dobutamine echo Poldermans, 1999 Post-op ischemia, cardiac death and events, death Atenolol, before surgery and through hospital stay 200, with or at risk for cardiac disease Mangano, 1996 Outcome Variables Study Drug Patients Study
  • 7. Results of the Review
    • 3 out of 4 studies found a decrease in peri-operative ischemia in beta-blocker treated patients.
      • NNT 2.5-6.7.
    • 2 out of 3 studies found a decrease in cardiac death in beta blocker treated patients.
      • NNT 3.2-12.7.
    • Size of effect varied by risk status of study population, with largest effect in patients with abnormal dobutamine echocardiograms.
  • 8. Effect of Atenolol on Mortality and Cardiovascular Morbidity After Non-Cardiac Surgery Mangano et al. NEJM 1996;335:1713-20.
    • Randomized, double blind, placebo controlled trial
    • 200 patients enrolled, 192 followed for two years.
    • Received IV atenolol 30 minutes prior to and after surgery, then transitioned to oral dosing.
    • Monitored during hospitalization and had six month, one year and two year evaluations.
  • 9. Patient Selection
    • Patients with or at risk for CAD at SF VAMC undergoing elective noncardiac surgery with GETA
      • Previous MI, typical angina, or atypical angina with positive stress test
            • OR
      • Two or more of the following risk factors
        • > 65 yo, hypertension, smoking, cholesterol >240 mg/dl, and diabetes.
    • Exclusion criteria: left BBB, pacemaker, ST-T wave abnormalities limiting ECG interpretation.
  • 10. Characteristics of Patients by Study Group 0.003 8 23 ACE-I use 0.05 19 30 Anti-hypertensive 0.02 8 18 Beta blocker use 0.38 59 63 At risk for CAD 0.38 42 36 CAD P Value Placebo Group (101) Atenolol Group (99) Charac-teristic
  • 11. Outcomes
    • Principle effect on mortality seen at 6-8 months, with 9% [3%,15%] ARR, NNT 11.
    • Benefit maintained up to two years, with 12% [7%,17%] ARR for death at end of follow-up period, 8% [4%, 12%] ARR for death from cardiac causes.
    • Atenolol treated group with 16% [10%, 22%] ARR for cardiac events at 2 years, NNT 6.
  • 12. Outcomes, Continued
    • Companion study found 40% lower incidence of ischemic events in seven days post-operative, but no difference in events pre- and intra-operatively.
    • More than 85% tolerated study drug, and 60% were able to receive the full dose
    • No difference in incidence of bradycardia, hypotension or bronchospasm between study groups.
  • 13. Potential Confounders
    • Atenolol group was more likely to be taking beta-blockers (14% vs. 7%) and ACE inhibitors (20% vs. 6%) at discharge.
      • Odds ratio for mortality at two years associated with use of these two drugs were not significant.
      • However, it is unclear if these variables were included in the statistical modeling of predictors of death.
  • 14. Potential Confounders, Continued
    • Statistics suggest treatment effect may only be seen in patients with diabetes.
      • Increased treatment effects seen in patients with DM (hazard ratio for pts with DM 0.25 compared to 0.4 for all patients).
      • Atenolol effect no longer significant when controlled for DM in multivariable analysis.
  • 15. Conclusions
    • Authors conclude that perioperative beta blockade is safe and effective in preventing mortality and cardiovascular events in patients with or at risk for CAD.
    • Rough estimate of cost, based on 1/5 th of effect seen in this study, cost is $2,500 per life-year saved.
  • 16. Critique of Study
    • Effect of potential confounders unclear
      • Diabetes
      • Use of anti-hypertensive medications
      • What variables were tested in the statistical model not stated.
    • Gender of patients not discussed.
    • Small sample size, with potential for non-significant differences in groups to have a confounding effect.
  • 17. JAMA Review – Summary Recommendations
    • While evidence exists to support use of beta-blockers perioperatively, there are substantially gaps in the data
      • Only five heterogenous RCTs with fewer than 600 patients support this finding.
      • Data is limited in patients with depressed ejection fraction or undergoing regional anesthesia or conscious sedation.
      • Effect of beta blockers in low risk patients unknown.
      • Best treatment regimen unclear, with no evidence one agent superior.
        • Do recommend starting 30 days before and continuing after surgery, with IV administration titrated immediately prior to surgery.
  • 18. Recommendations, Continued
    • Recommend differentiating low, intermediate and high risk groups based on clinical characteristics.
      • See Figure on p. 1441
    • Use of beta-blockers increases threshold for further testing to those with greater than 3 risk criteria or 1-2 and poor functional status.
    • Intermediate risk with good functional status can have surgery with beta blockade.
    • Low risk patients most likely do not benefit from beta blockade.
  • 19. The Next Steps…
    • Need larger RCT looking at effect on cardiac outcomes of perioperative beta blocker use across cardiac risk profiles.
    • If data continues to support its use, need to define ideal dosing regimen.
    • Need to incorporate data into existing peri-operative risk management algorithms.
    • In meantime, we may chose to forgo further testing in some patients who are candidates for beta blockers.
  • 20. Selected References
    • Auerbach AD, Goldman L. Beta blockers and reduction of cardiac events in noncardiac surgery. JAMA 2002;287:1435-44.
    • Boersma E, Poldermans D, Bax JJ, et al. Predictors of cardiac events after major vascular surgery: Role of clinical characteristics, dobutamine echocardiograph and beta blocker therapy. JAMA 2001;285:1865-1873.
    • Eagle KA. ACC/AHA guideline update for perioperative cardiovascular evaluation for non-cardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2002. American College of Cardiology website, www.acc.org/clnical/guidelines/perio/dirindex.htm.
    • Lee TH et al. Derivation and prospective Validation of a simple index for prediction of cardiac risk of major non-cardiac surgery. Circulation 1999;100:1043-49.
    • Mangano DT et al. Effect of atenolol on mortality and cardiovascular morbidity after non-cardiac surgery. NEJM 1996;335:1713-20.
    • Mangano DT et al. Association of perioperative ischemia with cardiac morbidity and mortality in men undergoing non-cardiac surgery. NEJM 1990;323:1781-8.
    • Wallace et al. Prophylactic atenolol reduces postoperative myocardial ischemia. Anesthesiology 1998;88:7-17.