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Journal Club

Journal Club. Lei Zhang PGY 3 7/16/09. Case. 55 y.o. F, PMH HTN, DM, TIA, and diverticulosis Had multitple diverticulitis, lower GIB in the past Scheduled to have elective colon resection in 2 wks Presented to the office for pre-op clearance Denied CP, SOB, swelling. Case.

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Journal Club

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  1. Journal Club Lei Zhang PGY 3 7/16/09

  2. Case • 55 y.o. F, PMH HTN, DM, TIA, and diverticulosis • Had multitple diverticulitis, lower GIB in the past • Scheduled to have elective colon resection in 2 wks • Presented to the office for pre-op clearance • Denied CP, SOB, swelling

  3. Case • HTN well controlled with Lisinopril and HCTZ • DM well controlled with Glipizide and Metformin • Also taking ASA and Zocor • Good functional status, able to climb 2 flight of stairs carrying grocery • Recent EKG/CXR within normal limits • Recent CBC, Chem 7 within normal limits

  4. Anything Else Needed Pre-operatively? Add Beta-blocker?

  5. Perioperative Beta Blocker use • Circulation, 2006 • Feringa and colleagues performed an observational cohort study of 272 vascular surgery patients • Higher doses of -blockers and tight heart rate (< 70 bpm) control associated with reduced perioperative myocardial ischemia and troponin release and improved long-term outcome

  6. Perioperative Beta Blocker use • J AM Coll Cardio, 2006 • Poldermans and colleagues randomly assigned 770 intermediate-risk patients to cardiac stress testing (n386) or no testing (n384) preoperatively • Concluded that cardiac testing can safely be omitted in intermediate-risk patients if beta blockers aimed at tight heart rate control are prescribed

  7. Perioperative Beta Blocker use • BMJ, 2005 • Donald Redelmeier & colleague performed retrospective cohort study in Canada in 37,151 asymptomatic patients older than 65 admitted for elective surgery (mainly abd & ortho procedure) • Patients receiving long-acting beta-blockers have lower perioperative cardiac risk than short-acting agent

  8. ACC/AHA Guideline for Pre-op Beta-blocker Use

  9. Perioperative Beta Blocker use • Am Heart J. 2006 • Yang & colleague performed a double-blind randomized controlled trial of perioperative metoprolol versus placebo in 496 patients undergoing vascular surgery • Metoprolol was not effective in reducing the 30-day & 6-month postop cardiac event rates. • Concluded that prophylactic use of perioperative beta-blockers in all vascular patients is not indicated

  10. Perioperative Beta Blocker use • BMJ, 2006 • Anne Benedicte Juul & colleague designed a randomized, controlled and blinded multicentre trial in 921 diabetic patients, age > 39, scheduled for major non-cardiac surgery • 100 mg metoprolol extended release or placebo given from the day before surgery to a max of 8 perioperative days • Conclusions: Perioperative metoprolol did not significantly affect mortality and cardiac morbidity

  11. Perioperative Beta Blocker use • BMJ, 2006 • Devereaux & colleague published a meta-analysis of randomized controlled trials in non-cardiac surgery pts • β blockers might prevent major cardiovascular events but increase the risk of hypotension & bradycardia

  12. Peri-operative Use of Beta-blocker Yes or NO

  13. POISE TRIAL • PeriOperative ISchemic Evaluation • Purpose of the trial: • Comparing the effect of extended-release metoprolol with that of placebo on 30-day risk of major cardiovascular events in patients with, or at risk of, atherosclerotic disease who were undergoing non-cardiac surgery.

  14. POISE TRIAL • Research question • Does peri-operative β-blocker regimen benefit noncardiac surgery pts without substantial harm? • Double-blinded, randomized, controlled, multi-center trial

  15. POISE TRIAL • Involved 8,351 pts and 190 hospitals in 23 countries • Study period 10/2002 – 7/2007 • Ethical approval for all participating sites obtained • Written informed consent obtained from all pts

  16. POISE TRIAL • Inclusion criteria • undergoing non-cardiac surgery • aged 45 years or older • expected length of hospital stay > 24 h • any one of the following criteria • hx of CAD • hx of PVD • Stroke

  17. POISE TRIAL • hospitalization for CHF within past 3 years • undergoing major vascular surgery • Or, any three of seven risk criteria • undergoing intrathoracic or intraperitoneal surgery • hx of CHF • hx of TIA • hx of diabetes • creatinine >175 μmol/L ( >2.0 mg/dL) • age >70 years • undergoing emergent or urgent surgery

  18. POISE TRIAL • Exclusion criteria • HR < 50 bpm • 2nd or 3rd AVB • Asthma • Receiving β blocker or planned to start one perioperatively • Prior adverse reaction to β blocker • CABG in the preceding 5 years with no ischemia • Low-risk surgical procedure • On verapamil

  19. POISE TRIAL • Patients were randomly assigned to two groups via a 24-h computerized randomization phone service • Participants, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation

  20. Trial Profile… Figure 1

  21. Table 2

  22. Method • 1st dose of the study drug (ie, oral extended-release metoprolol 100 mg or matching placebo) given 2–4 h before surgery • VS checked each time before medication to ensure HR > 50 bpm & SBP > 100 mm Hg

  23. Method • Within 6 h postop, pt received 1st post-op dose • 12 h after 1st post-op dose, start Metoprolol extended-release 200mg or placebo p.o. daily for 30 days • If HR <45bpm or SBP < 100, study drug withheld until recovered • Study drug was then restarted at 100mg daily

  24. Method • If HR consistently 45–49 bpm, SBP >100 mm Hg, delayed taking the study drug for 12 h • If unable to take p.o., study drug given by slow or rapid IV infusion q6h • Investigators were allowed to select either the slow or rapid IV infusion

  25. Method • Slow infusion • 15 mg of study drug in 25 mL NS over 60 min • HR & BP checked at 10, 30, and 60 min into the infusion • If HR/BP drop, study drug reduce to 10mg

  26. Method • Rapid infusion • 5 mg of the study drug IV over 2 min and repeated every 5 min for a total of 15 mg • ECG recorded 6–12 h postoperatively and on the 1st, 2nd , and 30th days • Troponin or CK-MB at 6–12 h postoperatively & on the 1st , 2nd , and 3rd days

  27. POISE TRIAL • Primary outcome • cardiovascular death • non-fatal MI • non-fatal cardiac arrest at 30 days

  28. Statistical Analysis • Study has 85% power to detect a relative risk reduction of 25% • All analyses used Cox proportional hazards models

  29. Table 3

  30. Results • Fewer in the metoprolol group reached the primary endpoint (hazard ratio 0·84, 95% CI 0·70–0·99, p=0·039) • Fewer patients in the metoprolol group had a non-fatal MI (hazard ratio 0·70, 95% CI 0·57–0·86; p=0·0008) • Fewer in the metoprolol group had cardiac revascularisation or developed new A fib

  31. Result • More in the Metoprolol group had a stroke (hazard ratio 2·17, 95% CI 1·26–3·74, p=0·0053) • More people receiving metoprolol died (1·33, 1·03–1·74, p=0·0317) • More pts receiving Metoprolol had significant hypotension and bradycardia

  32. Figure 2 MIs Primary Death Strokes

  33. Results • Median length of hospital stay was 8 (IQR 4–14) days in the Metoprolol group and 8 (4–15) days in the placebo group (p=0·4046) • The number of nights spent in ICU/CCU was much the same in the two groups

  34. Results • At discharge, Metoprolol group had • a lower mean HR(71·6 [SD 12·0]vs 78·6 [11·8]; p<0·0001) • lower mean SBP & DBP (129 [18·9]/72 [11·1] vs 131 [18·2]/74 [11·1]mm Hg; p<0·0001)

  35. Discussion • Why extended-release Metoprolol have increased risk of death and stroke? • Clinically significant hypotension, bradycardia and stroke contribute to the increasing risk of death

  36. Table 5

  37. Discussion • Sepsis or infection was the only cause of death that was significantly more common in Metoprolol group • Hypotension caused by β blockers could have predisposed pts to developing nosocomial infection

  38. Discussion • β blockers suppress tachycardia could delay the recognition of sepsis and infection, therefore delaying treatment, which might increase the risk of death

  39. Discussion • Pts receiving β-blocker who develop sepsis or infection might not have the capacity to mount enough response to sustain life or allow adequate delivery of antibiotics to tissue

  40. Discussion • POISE researchers also performed several meta-analysis of trials of periop Beta-blocker use • Decrease risk of non-fatal MI • Increase risk of death • Increase risk of non-fatal stroke

  41. Figure 4

  42. Conclusion

  43. Summary • Are the results valid? • Yes • Are the results important? • Yes • Can you apply the results to your patient? • Yes

  44. Validity • This is a large, multi-center, randomized, double-blind, controlled clinical trial • Both groups were comparable in terms of back ground information, type of surgery, anesthesia, and medications • Both groups were treated equally

  45. Validity • Confounding criteria were well-accounted between the two groups • Clear inclusion and exclusion criteria • Study has detailed medication administration and side-effect monitoring protocol • Follow-up was complete for majority of pts

  46. Validity • Although involving large of amount of pts and study personnel from 190 hospitals in 23 countries, the study was well regulated by central and on-site monitoring system • Problems found in Iran and Colombia were caught immediately and data excluded from the study

  47. Applicability • This is a large multi-country study, involving different racial, ethnic & economic population; it is safe to generalized the study results to our practice patients

  48. Significance • The study have enormous influence on current medicine practice • It challenged the currently popular concept of perioperative Beta-blocker use

  49. Significance • For every 15 patients in POISE trial, one had a cardiovascular death, non-fatal myocardial infarction, non-fatal cardiac arrest, or non-fatal stroke at 30-day follow-up

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