Betablockers and-reduction-of-cardiac-events-in-noncardiac4181

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  • Risk of bad outcomes very much depends on the patient population and your time frame. Over 1 million patients overall have perioperative cv morbidity, with cost over 20 billion – 500 million alone for periop myocardial infarction. Range of risk from 1% to greater than 30%. Estimate risk by referring for non-invasive or invasive testing and by using various guidelines for clinical estimating risk. Idea is having informed consent and weighing the need for surgery with the potential risks. Can postpone surgery to optimize medical conditions Revascularization has not been shown to have a favorable risk benefit ratio, and should only be done when the indication exists regardless of surgery. This has been studied retrospectively and using decision analysis models Little research has been done into management of risk perioperatively and how best to do this Often difficult to balance outcomes
  • Increase in myocardial events can be up to 21 fold. Compilation of studies suggests 28 x higher at six months, 20 at one year, and 14 at two years. Definition of ischemia is usually reversible st segment changes lasting at least one minute and at least 1 mm depression or 2 elevation. Post-operative ischemia has been found to be mostly silent – altered pain perceptions. May be demand ischemia. Also need to take into account overall hemodynamic compromise and rapid changes. Small studies of ccbs and nitroglycerin has mixed results, early studies of bbs were more promising and were pursued. Could there be another unrelated reason that beta blockers work??? We can’t prove causality. Other theories for why beta blockers work are suppressing lipolysis, promoting glucose use and thus decreasing the oxygen demand or increasing stability of plaques or increasing threshold for v fib.
  • Decreasing risk through beta blockers may increase threshold for non-invasive testing, depending on what level of comfort we have for intra-operative risks.
  • This is the study that made this all topical, even though it includes no new data. Designed to accumulate all information on this subject as generally guidelines on this issue have weak data.Performed a medline search augmented by reference lists from relevant articles and published recommendations on perioperative management. Limited to studies after 1980. Excluded one study because both groups received beta blockers. No statistical complication of the data
  • Busy slide, but basic point is that the data is all over the place. Many different study protocols, follow-up periods, patient populations and outcomes. All small studies. Note that poldermans and raby are two very high risk pt populations, whereas stone and urban are lower risk. Poldermans and stone are not randomized. Variable whether studies excluded those with or without beta blockers and those with asthma. Beta blocker use may blunt effect, or withdrawal may precipitate events. Most of them did determine the exact beta blocker dose on the basis of heart rate and blood pressure.   Raby – only 48 hour followup, outcome of myocardial ischemia (not a poem) very high risk pt population, pts could have beta blockers in addition to the study drug. Placebo group had higher use of bbs – suggests some unblinding had occur. Did look at infarctions etc but numbers are too small. Impractical to determine the target heart rate for everyone. Could be useful for higher risk patients   Urban – no difference between groups, was only one with regional anesthesia, mostly used managano criteria, intent to treat analysis. More extensive exclusions than with mangano. Not significant, had a lot of cross over. Regional anesthesia may have limited the events. Not significant – power analysis shows needs to have 240 patients. Only were looking after surgery – not given before. Had higher target heart rate of 80. follow up wascontinued until discharge from thei hospital   Poldermans – looked at outcome within 30 days with major vasc surgery, were very high risk patients – both clinically and by dobutamine echo. Excluded patients taking beta blockers or had extensive wall motion abnormalities. End point death from cardiac causes or non fatal MI. perioperative, designed to look at more immediate outcomes. Excluded asthma pts. Mi defined by enzymes AND q waves. No significant difference between study groups, was randomized. Relative risk of death or non fatal mi 0.09. study stopped early because of findings. Much higher risk group. Study was not blinded!!! – in first week had systematic screening but the next three weeks did it at discretion.   Stone – non-blinded, single dose looking only at introp anesthesia. Looking only at hypertensive pts. Excluded pts with asthma and pts with CAD, brady cardia or heart block. No difference between groups noted but not analyzed statistically. Looked at periop ischemia.
  • Urban was the non significant study, and had a relatively low risk cohort undergoing knee replacement with regional anesthesia, and had a higher target heart rate of 80 than the other studies, not very long follow up and had a lot of cross over between groups. In urban there is no significant different, managano some and poldermans a huge treatment effect. No adverse effects except 50% in stone et al required atropine.
  • Focus on one article. Most relevant to our patient population because are those at moderate risk for cardiac disease – not the really sick and not the healthy – the ones that are the most difficult to address. - the outcome is a poem – two years out how are they doing? All elective non-cardiac surgery, so a general patient population 6 patients died before discharge, one lost to followup and 1 not followed because never had surgery. Atenolol dose titrated to HR of 55, SBP 100, no CHF, 3 rd degree heart block or bronchospasm. Received 5-10 mg. After q12 or once a day oral 50-100 mg of atenolol (55-65 got 50). No treating physicians allowed to see administration of study drug. Received throughout hospitalization up to 7 days. Dose chosen based on ISIS data for after MI – same idea to prevent the sympathethic overload. Note perioperative data is actually included in a separate paper by Wallace published two years later, but is the same study population. Will focus on follow up data because that is the poem
  • Previous MI was postive history or ECG criteria of previous MMI, angina was ¾ of substernal CP, brought on by energy or stress, less than 15 minutes, relieved with nitro; atypical two of these with ischemic ecg response to exercise. Note asthma not a contraindication, also could be using beta blockers long term
  • No sig difference in specific cardiac risk factors, in cardiac disease history such as MI or history of dysrhythmia or CHF, no difference in age, duration or type of surgery. Htn issue could go either way – more treated or more at risk.
  • MI required new q waves, or peristant ST or t wave changes with elevation of CK and CK MB or eveidence of mi at autopsy or documentation in hospital records. Unstable angina severe precordial CP lasting at least 30 minutes, unresponsive to standard therapeutic manuevers, with tranisent st/t wave changes without q or enzymes. Death was considered due to cardiac cause if due to MI, dysrhythmia or CHF due to cardiac condition. Primary outcome all cause mortality at two years, secondary combined MI, unstable angina or CHF requiring hospital admission, revasc and death. Absolute numbers for mortality were 1 death vs 10 at 6-8 months, after 8 months no sig difference between the groups, at 2 years 9 vs 21 deaths. Cardiac outcomes benefit first seen at 6-8 months as well, data not given. Cardiac deaths were 4 vs 12. Cardiac events 16 vs 32.
  • This study bore out other studies that found that post op ischemia predicts mortality, as the risk of death over 2 years was 13 vs. 26% with or without ischemia. Note no dose analysis was done as it was the target heart rate that mattered. Expected to find no difference in event rates because of low event rates
  • Performed hazards ratio modeling where they looked for univariable predictors of two year mortality, and then those with p<.10 plugged into multivariable analysis.
  • This diabetes effect is not mentioned in the text of the article, and the test of whether atenolol effect is still significant when controlled for DM is not done. Not many DM pts, only 28 and 35. Other issue is how they did the statistical analysis. Not explicitly stated what variables they plugged into model. Univariable predictors atenolol, dm, post op ischemia, then plugged these into multivariable and got DM and atenolol.
  • 3 million surgical patients at risk, with 2% reduction with 2 additional years, cost 100 dollars per pt They make conclusions about safety based on small number of pts – we now know beta blockers are quite safe, but this has not been well addressed peri-operatively. (I.e this study only included 17 CHF pts)
  • Pretty good study design – randomized, poem, blinded, with clear results – except a few problems. Not stating what variables were tested is concerning for intraoperative complications 6% increase in CAD and 8% in prior MI in control group, not significant but could have an effect. Had good follow-up etc. Unclear how long the treatment effect goes out
  • Now back to the review article. Summary of the results from all the articles. Should be clear that even the best data in this area is sketchy. Data is heterogenous in outcome, pt population etc. Effect of beta blockers in low risk patients is unknown because no one has studied it. A recent observational study suggest little additional benefit in patients with no risk factors.
  • That being said, the authors of the JAMA paper do make a rather bold statement about use of this data in perioperative management, incorportating into risk stratification guidelines. Using data from two other studies – one observational and one a derived and prospectively validating cardiac risk predictor – came up with an algorithm for post-oping a pt. Use two criteria to risk stratify pts – the managano way and the prospectively validated way. There are lots of other criteria that are used – including age etc. used ot ifnd much more than history of aortic stenosis and arrhythemias were a big issue Lee criteria is any high risk procedure, ischemic heart disease, cerebrovascular disease, dm, and CRI of 2.0 or greater. Managano is other criteria used. Functional testing was pulled out of the blue, but ACC agrees with it. Some evidence of increased complications with decreased functional capacity. Consistent with other guidelines in that less than 3% risk is considered low risk – thus if we have predictors for intermediate risk with beta blockers that are less than 3% can skip testing. However, Use of beta blockers mentioned in most recent American College of Cardiology, but not incorporated in their algorithm as suggested above. – recommended mostly for very high risk patients. Study used to predict all this was observational, but were having major vascular surgery. NO mention is made of patients that fit the additional risk stratification part.
  • Need to incorporate into risk management algorithms, not just tag it on, as a way of lowering costs. In meantime, we should incorporate this into our pre-operative evaluation and recommendations, and remember that if we refer a pt to non-invasive testing often there is nothing we will do differently anyway based on the results, so just using beta blockers may be adequate.
  • Betablockers and-reduction-of-cardiac-events-in-noncardiac4181

    1. 1. Beta-Blockersand Reduction of Cardiac Events in Noncardiac SurgeryChristine Dehlendorf, MD Journal Club November 13, 2002
    2. 2. Context30 million patients per year have non-cardiacsurgery, and 3 million of these have or are at riskfor having cardiovascular diseaseConcern for cardiovascular disease the mostcommon reason for pre-operative consultationConsultations often limited to: Estimation of risk Postponing or canceling surgery Consideration of revascularization
    3. 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. 4. Relevance to the Family PhysicianImportant role in pre-operative evaluationsManaging pre and post-operative inpatients
    5. 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-operativebeta blocker use.Five studies from 1988 to 2000.Total of less than 600 patients.Very heterogenous data sources.
    6. 6. Review of StudiesStudy Patients Length of Study Drug Outcome Follow-up VariablesMangano, 200, with or at 2 years Atenolol, before Post-op1996 risk for cardiac surgery and through ischemia, disease hospital stay cardiac death and events, deathPoldermans 112, positive 30 days Bisoprolol, 37 days Cardiac death, 1999 dobutamine before and 30 days and non-fatal MI echo after surgeryRaby, 1999 26, pre-op 48 hours Esmolol, after surgery Myocardial ischemia by for 48 hours ischemia HolterStone, 1988 128, untreated To termination Atenolol, labetalol or Myocardial hypertensives of anesthesia oxprenolol, one oral ischemia dose before anesthesiaUrban, 129, with or at Until discharge Esmolol after surgery, Myocardial2000 risk for cardiac from hospital then changed to ischemia and
    7. 7. Results of the Review3 out of 4 studies found a decrease in peri-operative ischemia in beta-blocker treatedpatients. NNT 2.5-6.7.2 out of 3 studies found a decrease in cardiacdeath in beta blocker treated patients. NNT 3.2-12.7.Size of effect varied by risk status of studypopulation, with largest effect in patients withabnormal dobutamine echocardiograms.
    8. 8. Effect of Atenolol on Mortality andCardiovascular Morbidity After Non- Cardiac Surgery Mangano et al. NEJM 1996;335:1713-20.Randomized, double blind, placebo controlledtrial200 patients enrolled, 192 followed for two years.Received IV atenolol 30 minutes prior to andafter surgery, then transitioned to oral dosing.Monitored during hospitalization and had sixmonth, one year and two year evaluations.
    9. 9. Patient SelectionPatients with or at risk for CAD at SF VAMC undergoingelective 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 waveabnormalities limiting ECG interpretation.
    10. 10. Characteristics of Patients by Study GroupCharac- Atenolol Placebo P Valueteristic Group (99) Group (101)CAD 36 42 0.38At risk for 63 59 0.38CADBeta blocker 18 8 0.02useACE-I use 23 8 0.003Anti- 30 19 0.05hypertensive
    11. 11. OutcomesPrinciple 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-upperiod, 8% [4%, 12%] ARR for death fromcardiac causes.Atenolol treated group with 16% [10%, 22%]ARR for cardiac events at 2 years, NNT 6.
    12. 12. Outcomes, ContinuedCompanion study found 40% lower incidence ofischemic 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 doseNo difference in incidence of bradycardia,hypotension or bronchospasm between studygroups.
    13. 13. Potential ConfoundersAtenolol group was more likely to be takingbeta-blockers (14% vs. 7%) and ACEinhibitors (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. 14. Potential Confounders, ContinuedStatistics suggest treatment effect mayonly 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. 15. ConclusionsAuthors conclude that perioperative betablockade is safe and effective in preventingmortality and cardiovascular events in patientswith or at risk for CAD.Rough estimate of cost, based on 1/5th of effectseen in this study, cost is $2,500 per life-yearsaved.
    16. 16. Critique of StudyEffect 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 aconfounding effect.
    17. 17. JAMA Review –Summary RecommendationsWhile evidence exists to support use of beta-blockers perioperatively, there are substantiallygaps 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. 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. 19. The Next Steps…Need larger RCT looking at effect on cardiacoutcomes of perioperative beta blocker useacross cardiac risk profiles.If data continues to support its use, need todefine ideal dosing regimen.Need to incorporate data into existing peri-operative risk management algorithms.In meantime, we may chose to forgo furthertesting in some patients who are candidates forbeta blockers.
    20. 20. Selected ReferencesAuerbach AD, Goldman L. Beta blockers and reduction of cardiac events in noncardiacsurgery. JAMA 2002;287:1435-44.Boersma E, Poldermans D, Bax JJ, et al. Predictors of cardiac events after major vascularsurgery: Role of clinical characteristics, dobutamine echocardiograph and beta blockertherapy. 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 HeartAssociation Task Force on Practice Guidelines. 2002. American College of Cardiologywebsite, www.acc.org/clnical/guidelines/perio/dirindex.htm.Lee TH et al. Derivation and prospective Validation of a simple index for prediction ofcardiac 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 andmortality 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.

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