W. Scott Beattie MD PhD FRCPC
Future Directions in Beta Blocker Clinical Trials:
April 1 2014 2:30 PM
The World Health Organization estimates more than 230 million surgical
procedures are performed annually. Surgery is associated with a 60-day mortality
rate of 4% with wide variation noted between different health care systems
Perioperative cardiac events are a leading cause of this postoperative mortality. In
this lecture we will review the cardio-protective effects of perioperative beta
blockade, evidence that previous trials did not account and for newly appreciated
pathophysiologic relationships between beta-adrenergic antagonism and
perioperative anemia.
The evidence for the cardio-protective effects of perioperative beta-adrenergic
antagonism is irrefutable; Perioperative beta-blockade reduces the incidence of
perioperative myocardial infarction. 1 However the Peri-Operative ISchemic
Evaluation (POISE) trial drew attention to concomitant safety issues. In POISE,
acutely instituted metoprolol reduced perioperative MI yet doubled the incidence of
postoperative strokes, deaths due to sepsis, and increasing all-cause mortality by
30%. 2 These safety issues had actually been alluded to in a meta-analysis of all betablocker trials prior to POISE. 3
In the POISE trial, stroke and death were both associated, in post hoc analyses, with
a higher incidence of hypotension, bradycardia requiring therapy and major blood
loss. The POISE data is limited in this respect since hypotension was never explicitly
defined nor were the absolute blood pressure changes presented. In addition, the
lowest hemoglobin levels and the total amount of red cell units transfused were not
presented. However, major blood loss was defined as 2 or more units of blood
transfused peri-operatively. We submit that these are important deficiencies.
Perioperative anemia has been independently associated with major postoperative
adverse outcomes. Acute perioperative anemia is common, occurring in over 30% of
elective surgical patients
Evidence from animal experiments suggests that the preservation of vital tissue
oxygenation during acute anemia is mediated in part by β2 adrenergic controlled
vascular resistance. Metoprolol has been shown to attenuate this mechanism and
decreases the safety profile of this widely used cardio-protective drug.
Currently a large proportion of patients presenting for major surgery are also
prescribed beta-blockers as a direct result of the various AHA/AAC management
guidelines.4-7 Twenty to forty percent of moderate to high-risk surgical patients,
who present for elective surgery are chronically beta blocked. Many of these
patients require beta blockade to manage major cardiovascular comorbidities or
have been placed on them due to existing best practice guidelines. Over 70% of
these patients receive Metoprolol. More beta-1 selective agents are available that
have been shown to better preserve vital organ function. We argue that the next
logical step is to conduct a randomized clinical trial in high cardiac risk, chronically
beta blocked patients.
1.
Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH.
Perioperative beta blockers in patients having non-cardiac surgery: A metaanalysis. Lancet. 2008;372:1962-1976
2.
Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D,
Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Malaga G, Avezum A,
Chan M, Montori VM, Jacka M, Choi P. Effects of extended-release metoprolol
succinate in patients undergoing non-cardiac surgery (poise trial): A
randomised controlled trial. Lancet. 2008;371:1839-1847
3.
Devereaux PJ, Beattie WS, Choi PT, Badner NH, Guyatt GH, Villar JC, Cina CS,
Leslie K, Jacka MJ, Montori VM, Bhandari M, Avezum A, Cavalcanti AB, Giles
JW, Schricker T, Yang H, Jakobsen CJ, Yusuf S. How strong is the evidence for
the use of perioperative beta blockers in non-cardiac surgery? Systematic
review and meta-analysis of randomised controlled trials. BMJ.
2005;331:313-321
4.
Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof EL, Fleischmann KE,
Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith
SC, Jr., Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA,
Ettinger SM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW,
Nishimura R, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW. Acc/aha
2007 guidelines on perioperative cardiovascular evaluation and care for
noncardiac surgery: Executive summary: A report of the american college of
cardiology/american heart association task force on practice guidelines
(writing committee to revise the 2002 guidelines on perioperative
cardiovascular evaluation for noncardiac surgery) developed in collaboration
with the american society of echocardiography, american society of nuclear
cardiology, heart rhythm society, society of cardiovascular anesthesiologists,
society for cardiovascular angiography and interventions, society for
vascular medicine and biology, and society for vascular surgery.
J.Am.Coll.Cardiol. 2007;50:1707-1732
5.
Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS,
Foody JM, Gerber TC, Hinderliter AL, King SB, 3rd, Kligfield PD, Krumholz
HM, Kwong RY, Lim MJ, Linderbaum JA, Mack MJ, Munger MA, Prager RL,
Sabik JF, Shaw LJ, Sikkema JD, Smith CR, Jr., Smith SC, Jr., Spertus JA, Williams
SV, American College of Cardiology F, American Heart Association Task Force
on Practice G, American College of P, American Association for Thoracic S,
Preventive Cardiovascular Nurses A, Society for Cardiovascular A,
Interventions, Society of Thoracic S. 2012 accf/aha/acp/aats/pcna/scai/sts
guideline for the diagnosis and management of patients with stable ischemic
heart disease: A report of the american college of cardiology
foundation/american heart association task force on practice guidelines, and
the american college of physicians, american association for thoracic surgery,
preventive cardiovascular nurses association, society for cardiovascular
angiography and interventions, and society of thoracic surgeons. Journal of
the American College of Cardiology. 2012;60:e44-e164
6.
Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG,
Konstam MA, Mancini DM, Rahko PS, Silver MA, Stevenson LW, Yancy CW.
2009 focused update: Accf/aha guidelines for the diagnosis and management
of heart failure in adults: A report of the american college of cardiology
foundation/american heart association task force on practice guidelines:
Developed in collaboration with the international society for heart and lung
transplantation. Circulation. 2009;119:1977-2016
7.
Writing Group M, Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB,
Estes NA, 3rd, Ferguson TB, Jr., Hammill SC, Karasik PE, Link MS, Marine JE,
Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy
PD, Writing Committee M, Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA,
3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes
DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW,
Sweeney MO, Members AATF, Anderson JL, Jacobs AK, Halperin JL, Albert
NM, Creager MA, DeMets D, Ettinger SM, Guyton RA, Hochman JS, Kushner
FG, Ohman EM, Stevenson W, Yancy CW, American College of Cardiology F,
American Heart Association Task Force on Practice G, American Association
for Thoracic S, Heart Failure Society of A, Society of Thoracic S. 2012
accf/aha/hrs focused update of the 2008 guidelines for device-based therapy
of cardiac rhythm abnormalities: A report of the american college of
cardiology foundation/american heart association task force on practice
guidelines. The Journal of thoracic and cardiovascular surgery.
2012;144:e127-145