Journal Club Lei Zhang PGY 3 71609 Case
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 • 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
Anything Else Needed Pre-operatively? Add Beta-blocker?
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 longterm outcome
Perioperative Beta Blocker use • J AM Coll Cardio, 2006 • Poldermans and colleagues randomly assigned 770 intermediate-risk patients to cardiac stress testing (n 386) or no testing (n 384) preoperatively • Concluded that cardiac testing can safely be omitted in intermediate-risk patients if beta blockers aimed at tight heart rate control are prescribed
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 betablockers have lower perioperative cardiac risk than short-acting agent
ACC/AHA Guideline for Pre-op Beta-blocker Use
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
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
Perioperative Beta Blocker use • BMJ, 2006 • Devereaux & colleague published a metaanalysis of randomized controlled trials in non-cardiac surgery pts • β blockers might prevent major cardiovascular events but increase the risk of hypotension & bradycardia
Peri-operative Use of Beta-blocker Yes or NO
POISE TRIAL • Peri. Operative ISchemic Evaluation • Purpose of the trial: – Comparing the effect of extendedrelease 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.
POISE TRIAL • Research question – Does peri-operative β-blocker regimen benefit noncardiac surgery pts without substantial harm? • Double-blinded, randomized, controlled, multi-center trial
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
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
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/d. L) age >70 years undergoing emergent or urgent surgery
POISE TRIAL • Exclusion criteria – – – – HR < 50 bpm 2 nd or 3 rd 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
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
Trial Profile… Figure 1
Table 2
Method • 1 st 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
Method • Within 6 h postop, pt received 1 st post-op dose • 12 h after 1 st post-op dose, start Metoprolol extended-release 200 mg or placebo p. o. daily for 30 days • If HR <45 bpm or SBP < 100, study drug withheld until recovered • Study drug was then restarted at 100 mg daily
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 q 6 h • Investigators were allowed to select either the slow or rapid IV infusion
Method • Slow infusion – 15 mg of study drug in 25 m. L NS over 60 min – HR & BP checked at 10, 30, and 60 min into the infusion • If HR/BP drop, study drug reduce to 10 mg
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 1 st, 2 nd , and 30 th days • Troponin or CK-MB at 6– 12 h postoperatively & on the 1 st , 2 nd , and 3 rd days
POISE TRIAL • Primary outcome – cardiovascular death – non-fatal MI – non-fatal cardiac arrest at 30 days
Statistical Analysis • Study has 85% power to detect a relative risk reduction of 25% • All analyses used Cox proportional hazards models
Table 3
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
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
Figure 2 MIs Primary Strokes Death
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
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)
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
Table 5
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
Discussion • β blockers suppress tachycardia could delay the recognition of sepsis and infection, therefore delaying treatment, which might increase the risk of death
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
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
Figure 4
Conclusion
Summary • Are the results valid? – Yes • Are the results important? – Yes • Can you apply the results to your patient? – Yes
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
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
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
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
Significance • The study have enormous influence on current medicine practice • It challenged the currently popular concept of perioperative Betablocker use
Significance • For every 15 patients in POISE trial, one had a cardiovascular death, nonfatal myocardial infarction, non-fatal cardiac arrest, or non-fatal stroke at 30 -day follow-up
Significance • Suggest that the addition of perioperative Beta-blocker potentially has serious risks • Lead to the further question of who will benefit from Beta-blocker and who will not?
Thank You
ACC/AHA Guideline for Preop Eval for Noncardiac Surgery • Pts with active cardiac conditions, indicate major clinical risk – unstable coronary syndromes, • acute MI < 7 days • recent MI > 7 days but </= 1 month with evidence of ischemia • unstable or severe angina – decompensated heart failure, – significant arrhythmias – severe valvular disease
ACC/AHA Guideline for Preop Eval for Noncardiac Surgery • Pts with clinical risk factors – history of heart disease, • hx MI or Q waves by ECG – history of compensated or prior CHF – history of cerebrovascular disease, TIA, stroke – diabetes mellitus, preop use of insulin – renal insufficiency, preop Cr >2. 0
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