Controversies in Hospital Medicine: Beta Blockers, Heparin and Hypergylcemia

1
Controversies in Hospital Medicine Beta
Blockers, Heparin and Hypergylcemia

• Jeff Glasheen, MD
• Director, Hospital Medicine Program
• University of Colorado Hospital
• Associate Professor of Medicine
• University of Colorado Denver

2
To block or not to block

• Should I beta block my patient peri-operatively?

3
What is the next best step?
64 yo man w/ DM CAD undergoing R THA Exam
131/69,72,10 Otherwise normal Meds Glargine,
Lispro, ACE, Amlodipine, ASA

• A) Metoprolol to HR lt 60 bpm
• B) Metoprolol to HR 60-80 bpm
• C) Metoprolol to HR 80-100 bpm
• D) Metoprolol not indicated

4
Perioperative Beta Blockade Beneficial

• 1996 200 noncardiac surgery pts1
• Atenolol DOS and t/o hosp stay
• 50 reduction in mortality at 2 years
• 1999 112 high risk vascular surgery pts2
• Bisoprolol 1 wk prior and t/o hosp stay
• 90 reduction in cardiac death/MI at 28 days
• 2000 107 noncardiac surgery pts3
• Esmolol DOS and 48 hours post-op
• 67 reduction in postoperative MI
• 2001 1000 lower risk vascular surgery pts4
• 70 reduction in adjusted RR of MI

1Mangano NEJM 19963351713-1720 2Poldermans NEJM
19993411789-1794 3Urban Anesth Analg
2000901257-1261 4Boersma JAMA 20012851865-1873
not statistically significant
5
Since the 2001 Report

• 2005 POBBLE1
• Metoprolol in 103 vascular surgery patients
• No effect of beta blockers on cardiac events
• 2005 Meta-analysis2
• 22 RCT of periop BB
• Non-statistically sign trend toward better
  outcomes at 30 days
• ?risk of intraop hypotension and bradycardia
• Concluded that use of PBB requires caution

1 Brady, J Vasc Surg 200541602-609 2 Devereaux,
BMJ 2005331313-321
6
Since the Meta-analysis

• 2005 Large observational trial
• gt600,000 patients undergoing major noncardiac
  surgery
• Compared pts who received BB w/in 2d of
  hospitalization vs. those that did not
• Only high risk patients benefited from
  perioperative BB

Lindenauer NEJM 2005353349-3361
7
Beta Blockers Raising the Threshold for Use
Revised Cardiac Risk Index High risk
surgery Coronary artery dz Cerebrovascular
dz Chronic kidney dz Diabetes mellitus
Lindenauer NEJM 2005353349-3361
8
Beta Blockers Raising the Threshold for Use
No beta, unless CAD
Beta
Lindenauer NEJM 2005353349-3361
9
Since the Observational Study

• 2006 MAVS1
• RCT vascular surg, metoprolol (246) vs. Placebo
  (250)
• No difference 30 d MI, USA, CHF, Death 10.2 v
  12
• Significantly more intraop hypotension and
  bradycardia
• No titration of med HR 69 bpm vs. 79 bpm
• 2006 DIPOM2
• RCT 921 diabetics, major non-cardiac surgery
• No effect of metoprolol 100 mg daily, ave of 5
  days
• No titration HR in met 75 bpm

1Yang, Am Heart J 2006152983-90 2Juul, BMJ
20063321482-8
10
Titration is the Key!

• 2006 Observational study1
• 272 vascular surgery pts, target HR 55-70 bpm
• Overall
• 31 had myocardial ischemia
• 16 had troponin release
• 24 mortality rate at 2.6 years
• Higher ß-blocker dose assoc w/ lower MI death
• Conversely, higher HR assoc w/ higher MI death
• Titration seems to matter
• 2006 DECREASE-II2
• 770 vascular surgery pts, intermediate cardiac
  risk
• DSE (386)?intervention v. no test (384)
• All patients beta blocked to target HR 60-65
• No difference in DSE v. No test group
• HR lt 65 v. HR gt 65 (1.3 v. 5.2 death/MI rate)

1 Feringa, Circulation 20061141344-92
Poldermans, JACC 200648964-9
11
Perioperative Beta Blocker DosingACC/AHA
Recommendation

• PBB probably good
• High risk patients
• Start wks b/4 surg
• Titration

• Available evidence suggests, but does not prove
  that, when it is possible, BB should be started
  several days or weeks before elective surgery,
  with the dose titrated to achieve a resting HR
  b/w 50-60 bpm, to assure that the patient is
  indeed receiving the benefit of BB and should
  continue during the intraoperative and post
  operative period to maintain a HR lt 80 bpm.
• No definitive evidence that one drug is best.

Fleisher, JACC 2006472343-2354
12
POISE Trial

• 8351 pts w/ or at risk of CAD
• 4174 metoprolol vs. 4177 placebo
• Metoprolol CR 100 mg pre
• Metoprolol CR 100 mg 6 hrs post
• Metoprolol CR 200 mg daily x 30 days

PBB ? MI and cardiac death but ? overall
mortality and stroke
Metoprolol Placebo
MI 3.6 5.1
Composite 5.8 6.9
Total mortality 3.1 2.3
Stroke 1.0 0.5

• Started right b/4 surg
• High initial dose
• No dose titration
• Probably doesnt
• change recs yet

All comparisons statistically significant
Devereaux, Lancet online May 13, 2008
13
What is the next best step?
64 yo man w/ DM CAD undergoing R THA Exam
131/69,72,10 Otherwise normal Meds Glargine,
Lispro, ACE, Amlodipine, ASA

• A) Metoprolol to HR lt 60 bpm
• B) Metoprolol to HR 60-80 bpm
• C) Metoprolol to HR 80-100 bpm
• D) Metoprolol not indicated

14
Anti-coagulation

• Should I heparinize a patient with an acute
  stroke?

15
What is the next best step?
68 yo woman w/ DM, hyperlipidemia CAD 6 hrs
R-sided UEgtLE weakness, aphasia Meds Glargine,
Lispro, ACE, simvastatin, ASA

• A) UFH at therapeutic doses
• B) LMWH at therapeutic doses
• C) Warfarin at therapeutic doses
• D) UFH/LMWH at VTE prophylactic doses
• E) No anticoagulation

16
Background

• 700,000 strokes/yr in US
• 85 are ischemic
• Most are caused by acute blood clots in an artery
  in the brain
• Recurrent stroke is common?1-13
• Post-stroke DVT, PE are also common
• Anticoagulants used in acute stroke for gt 50 yrs
• Increased risk of intra- extra-cranial bleeding
• Controversy
• When to start? Which agent?
• Which route? Bolus vs. drip?
• Level of anticoagulation
• Type of stroke?cardioembolic vs.
  non-cardioembolic

17
Anticoagulants for Acute Ischemic Stroke

• Question What is the effect of anticoagulation
  (AC) in the early treatment (lt 14 days) of
  acute stroke?
• Design Sys rev of 24 RCT early AC v. control in
  ischemic CVA

Cochrane Review 2008
18
Results

• 24 trials (23,748 pts)
• 13/24 enrolled w/in 48 hours
• Duration of AC 1-2 weeks in 20 1 mo in 4
• UFH 8, LMWH 8, VKA 2, hepranoid 3, DTI 3
• Studies of variable quality/design
• Randomization, dosing, CT scans, asses DVT,
  antiplatelet use, duration of f/u
• Variability in outcomes measured
• CVA, ICH, ECH, death, death and dependency, DVT,
  PE

Cochrane Review 2008
19
Recurrent Ischemic Stroke or ICH

• Ischemic stroke
• 11 trials (21,605 pts)
• ? ischemic stroke (0.76, 0.65-0.88)
• NNT 108

• Intracranial hemorrhage
• 16 trials (22,943 pts)
• Increased rate of ICH (2.55, 1.95-3.33)
• NNH 131

AC reduces ischemic stroke AC increases ICH in
dose dependent fashion
Cochrane Review 2008
20
Post-Stroke DVT/PE

• DVT
• 10 trials (916 pts)
• Reduced DVT rate (0.21, 0.15-0.29)
• NNT 114

• PE
• 14 trials (22,544 pts)
• Reduced PE rate
• (0.6, 0.44-0.81)
• NNT 127

AC reduces DVT AC reduces PE
Cochrane Review 2008
21
Death Dependency

• 8 trials (22,125 pts)
• No evidence that AC reduced death or dependency
  (0.99 0.93-1.04)
• Subgroup
• No difference based on drug, dosing (proph v.
  adjusted)

Cochrane Review 2008
22
Anticoagulants for Acute Ischemic Stroke

• Question What is the effect of anticoagulation
  (AC) in the early treatment (lt 14 days) of
  acute stroke?
• Design Sys rev of 24 RCT early AC v. control in
  ischemic CVA
• Results Reduced Ischemic strokes, NNT 108
• DVT, NNT 114
• PE, NNT 127
• Increased Intracranial bleed, NNH 131
• Extracranial bleed, NNH 128
• No change in death or dependency
• Conclusion AC doesnt reduce risk of stroke,
  death or disability
• Cardioembolic, atrial fib, large vessel
  atherosclerosis, vertebrobasilar, cresendo,
  carotid dissection
• Lower rate of VTE offset by similar increase
  in ECH
• Comment Data dont support use of any form of AC
  w/in 14 d of CVA
• Low dose UFH/LMWH ? VTE but slightly ? risk of
  ICH ECH

Cochrane Review 2008
23
What is the next best step?
68 yo woman w/ DM, hyperlipidemia CAD 6 hrs
R-sided UEgtLE weakness, aphasia Meds Glargine,
Lispro, ACE, simvastatin, ASA

• A) UFH at therapeutic doses
• B) LMWH at therapeutic doses
• C) Warfarin at therapeutic doses
• D) UFH/LMWH at VTE prophylactic doses
• E) No anticoagulation

24
Hyperglycemia

• How should hyperglycemia be managed in the
  hospitalized patient?

25
What is the next best step?
49 yo man w/ DM Admitted to ward with CAP, BS
180 mg/dL Meds Metformin, Glyburide

• A) Continue home meds alone
• B) Continue home meds w/ sliding scale insulin
• C) Substitute sliding scale insulin alone
• D) Substitute basal-bolus insulin regimen

26
Blood Glucose Targets
Setting Blood Glucose Target
SICU Close to 110 mg/dl lt140 mg/dl
MICU lt140 mg/dl
Med-Surg lt126 mg/dl fasting All lt180-200
ADA Guideline Diabetes Care 200932S13-71
27
Diabetic Armamentarium
Class Example Comment
Sulfonylureas Glyburide Hypoglycemia if NPO
Biguanide Metformin Lactic acidosis w/ AKI
Thiazolidinedione Pioglitazone Increased fluid retention
Meglitinides Repaglinide Parandial med often NPO
GLP-1 Analogs Exenatide Parandial med often NPO
DPP-IV inhibitors Sitagliptin Parandial med often NPO
a-glucosidase Inh Acarbose Parandial med often NPO
Which leaves us with insulin...
ADA Guideline Diabetes Care 200932S13-71
28
RABBIT-2 Changes in BG Concentration Basal-Bolus
vs. SSI Regimen
N 130 hospitalized insulin-naive T2DM patients
240
SSI
Basal-bolus
220
200



180



BG (mg/dL)

160
140
Mean BS lt 140 66 of Basal-Bolus 38 of SSI No
diff in hypoglycemia
120
100
Admit 1 2 3 4 5 6
7 8 9 10 Days
P lt 0.01, P lt 0.05 vs. basal-bolus RABBIT
Randomized Study of Basal-Bolus Insulin Therapy
in the Inpatient Management of Patients With Type
2 Diabetes
Umpierrez GE et al. Diabetes Care. 2007302181.
29
Howd they do that?

• BS 140-200 0.4 u/kg/d
• BS 201-400 0.5 u/kg/d
• ½ given as long-acting
• ½ given as short-acting divided b/4 meals
• 100kg patient, BS 180
• 100 x 0.4 40 units
• 20 units glargine
• 7 units glulisine before each meal

• If fasting BS gt 140
• ? glargine by 20
• If fasting BS lt 70
• ? glargine by 20
• If pre-meal BS gt 140
• Correctional glulisine given

Generally d/c orals Dont use SSI Basal-bolus
insulin
Umpierrez GE et al. Diabetes Care. 2007302181.
30
What is the next best step?
49 yo man w/ DM Admitted to ward with CAP, BS
180 mg/dL Meds Metformin, Glyburide

• A) Continue home meds alone
• B) Continue home meds w/ sliding scale insulin
• C) Substitute sliding scale insulin alone
• D) Substitute basal-bolus insulin regimen

31
Conclusions

• Perioperative Beta blockers
• High risk patients (RCRI gt/ 2)
• Start weeks before
• Titrate to HR lt 60 bpm
• Heparin in acute stroke doesnt add benefit
• Consider low dose SQ UFH for VTE prophylaxis
• Basal-bolus insulin best achieves BG control
• Goal lt140 for SICU/MICU lt 180 for med-surg pts

32
(No Transcript)
33
Hospital Mortality Rate and Mean Glucose Levels
in Critically Ill Patients
Mortality Rate ()
Mean Glucose Value (mg/dL)
Retrospective review of 1,826 consecutive
intensive care unit patients. Krinsley JS. Mayo
Clin Proc. 20037814711478.
34
Hyperglycemia Is an Independent Marker of
Inpatient Mortality Risk
P lt 0.01
P lt 0.01
In-hospital Mortality Rate ()
New Hyperglycemia
Known Diabetes
Normoglycemia
Umpierrez GE, et al. J Clin Endocrinol Metab.
200287978982.
35
Current Practice

• Scenarios Neurologist AC Use
• Stroke in evolution 51
• Vertebrobasilar CVA 30
• Carotid territory CVA 31
• Multiple TIAs 47
• Atrial fibrillation and CVA 88

Al-Sadt Stroke 2002331574-77
36
Conclusions

• AC is not recommended to reduce risk of death,
  disability or recurrent stroke
• AC is not recommended in any specific sub-group
  after ischemic stroke
• Cardioembolic, atrial fib, large vessel
  atherosclerosis, vertebrobasilar, cresendo,
  carotid dissection
• SQ UFH or low dose LMWH may be used for VTE
  prophylaxis in high-risk patients but
  non-pharmacologic/aspirin therapy may be just as
  good w/o risk of bleeding

AHA Guideline Stroke 2007381655-711 Cochrane
Review 2008
37
Blood Glucose Targets
Setting Blood Glucose Target
SICU Close to 110 mg/dl lt140 mg/dl
MICU lt140 mg/dl
Med-Surg lt126 mg/dl fasting All lt180-200
Data for SICU pts strongest Data for MICU pts
less strong M/S little evidence for intervention
ADA Guideline Diabetes Care 200932S13-71