Choosing Wisely

Steven Sloan, MD, PhD

Boston Children’s Hospital &

Harvard Medical School

Choosing Wisely Campaign

• Initiative of American Board of Internal Medicine Foundation (ABIM)

• Aims to promote conversations between providers and patients promoting care that is supported by evidence

• National medical professional organizations contribute to campaign

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AcknowledgementsGroup Effort

• Jeannie Callum, M.D. Univ. of Toronto• Mike Murphy, MD, Univ. of Oxford, UK• Jonathan H. Waters, M.D. Univ. of

Pittsburgh• Beth Shaz, MD, New York Blood Center

AABB’s Choosing Wisely Statements

1. Don’t transfuse more units of blood than absolutely necessary

2. Don’t transfuse red blood cells for iron deficiency without hemodynamic instability

3. Don’t use blood products to reverse warfarin

4. Don’t perform serial blood counts on clinically stable patients

5. Don’t transfuse O-negative blood except to O-negative patients and in emergencies for women of child-bearing potential of unknown blood group

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1. Don’t transfuse more units of blood than absolutely necessary

Red cell issues per 1,000 population

0

10

20

30

40

50

60

USA Canada England

Bloo

d U

tiliz

ation

Per

1,0

00 P

opul

ation

CY08 CY10 CY11 CY12 CY13 (est.)

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Transfusion-related fatalitiesreported to the FDA 2009-13

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RCTs of restrictive v liberal transfusion

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• 4 high quality large RCTs of restrictive v liberal transfusion• Clinical scenarios: ICU, cardiac surgery, hip fracture, and

upper GI bleeding• Hb thresholds: 7 v 10; 8 v 10 x 2; 7 v 9g/L• Good separation of Hb in restrictive v liberal transfusion • Consistent difference in % patients transfused

Evidence of benefit with use of restrictive strategy (adults)

Outcome No of patients (studies)

Risk ratio (RR)

Absolute risk difference

No. of patients needing transfusion

6125 (17 studies)

RR 0.61 (0.52 to 0.72)

377 fewer

No. of units transfused

2715 (8 studies) - 1.19 units lower (1.85 to 0.53 lower)

30 day mortality 4979 (11 Studies)

RR 0.85 (0.070 to 1.03)

11 fewer

Reduction in mortality using data from RCTs evaluating Hb trigger < 7g/dl

Am J Med 2014;127:124-131

Guidelines for red cell transfusion

(Goodnough LT, Levy JH & Murphy MF. Lancet 2013; 381:1845-54)

• A restrictive threshold (7.0-8.0g/dL) should be used for the vast majority of hospitalized, stable patients without evidence of inadequate tissue oxygenation (evidence supports a threshold of 8.0g/dL in patients with pre-existing cardiovascular disease)

• Transfusion decisions should be influenced by symptoms and hemoglobin concentration

Don’t transfuse more units of blood than absolutely necessary

Variation in blood usage(Frank S et al. Transfusion 2013; 53:3052-59)

Specialty A

Specialty B

Specialty C

Specialty D

Specialty E

Specialty F

Specialty G

Specialty H

Specialty I

Trigger: lowest HbTarget: last Hb before discharge

Horizontal bars are the Hb trigger to target range for all transfused patients

Ideally:Trigger: pre-Tx HbTarget: post-Tx Hb

Blood ordering using CPOE

May 12Jan 12July 11Dec 10-May 11

Num

ber

of e

vent

s

Thanks to Mark Yazer, Pittsburgh

Implementation of single unit transfusion policy supported by CPOE

(Yerrabothala S et al. Transfusion 2014 epub)

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Implementation of single unit transfusion policy supported by CPOE

(Yerrabothala S et al. Transfusion 2014 epub)

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Implementation of single unit transfusion policy supported by CPOE

(Yerrabothala S et al. Transfusion 2014 epub)

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• Single unit red cell transfusions should be the standard for non-bleeding hospitalized patients

• Additional units should only be prescribed after re-assessment of the patient and their Hb

Don’t transfuse more units of blood than absolutely necessary

Choosing Wisely 2: Iron deficiency and iron deficiency anemia

Case

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38 y.o. who had just completed a 10K fun run the day before presented to the ER for dysfunctional uterine bleeding. Her hemoglobin on presentation was 5.8 gm/dL. She was subsequently transfused 2 units of PRBCs.

Percent of persons with iron deficiency (based on the body iron model):

• Children age 1-2 years: 14%

• Children age 3-5 years: 4%

• Females age 12-19 years: 9%

• Females age 20-49 years: 9%

Anemia in the Elderly

• 10% of men > 65 y.o.

• 11% of women > 65 y.o.

• > 20% for elderly above 85 y.o.

Guralnik JM, et al. Blood. 2004;104:2263-2268.

Anemia in the Elderly

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UA = Unexplained anemiaACI = Anemia of Chronic Inflammation

Guralnik JM et al. Blood 2004;104:2263

Weeks of pregnancy

Percent

of

normal

Iron Deficiency Anemia of Pregnancy

Postpartum iron deficiency and iron deficiency anemia

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Bodnar LM et al. J Nutr 2002;132:2298-2302

Good Medicine

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82 y.o. presented for total hip replacement discovered to have iron deficiency anemia. Medical history significant for daily naproxen use because of painful osteoarthritis. Work up revealed a gastric ulcer.

Note: anticoagulants routine in post operative joint replacement patients.

Incidence of Peptic Ulcer bleeding

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Incidence of 1% per patient-year of NSAID users will hemorrhage

Arlt et al. Langenbeck’s Arch Surg 2001; 386:75

Lower GI Bleeding in Elderly Patients

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Akhtar AJ. J Am Med Dir Assoc 2003;4:320

• Acute Anemia

– Hypotension

– Tachycardia

Anemia and Hemodynamic Instability

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Transfusion Band Aid

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Consequences of Iron deficiency

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Bodnar LM et al. Am J Obstet & Gynecol 2005;193:36-44

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2011 National Blood Collections and Utilization Survery, DHHS

Intravenous Iron Cost comparison to Allogeneic Blood

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Munoz M et al. Blood Transfusion 2014;12:40

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2 ¢ per 65 mg

3. Don’t routinely use blood products to reverse warfarin

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Risk of bleeding from warfarin

• 15% annual risk of a bleeding event• 1-3% annual risk of major bleeding

(hospitalization or death)• 0.25-1.0% annual risk of intracranial

hemorrhage

1. Linkins et al. Ann Intern Med 2003; 139: 893-900.2. Kearon et al. Chest 2012; 141 (2 suppl): e419S-e494S.3. Palareti et al. Lancet 1996; 348: 423-428.

Atrial fibrillation is common

1. Barrios et al. Rev Esp Cardiol 2012; 65:47-53.

If both atrial fibrillation & bleeding from warfarin are common…and the aging of the population

Then this is a common clinical situation where we must know exactly

what to do

When should you consider reversing with a blood product?

• Caveats:– We don’t know if reversal with blood products

impacts clinically relevant outcomes– Intravenous vitamin K must be given

concurrently as both prothrombin complex concentrates and plasma only last 6 hours

– The choice of the blood product is beyond the scope of this talk

1. Dowlatchahi et al. Stroke 2012;43:1812-7.

When should you consider reversing with a blood product?

• Limb or life-threatening bleeding– Intracranial hemorrhage– Pericardial bleed

• Emergency surgical procedure in the next 6 hours– Not just because the surgeon has operating

room time in 1 hour– Traumatic rupture of a spleen, perforated

viscous, ruptured aneurysm

Substantial proportion of plasma is used inappropriately to reverse warfarin

1. Tinmouth et al. Transfusion 2013;53:2222-9.

Warfarin accounts for 20% of plasma use(in the PCC/FFP era in Ontario)

1. Tinmouth et al. Transfusion 2013;53:2222-9.

Vitamin K works fasterthan you might realize

The factors are already synthesized & just need a final conversion step

Intravenous vitamin K is safe

• Some clinicians (and nurses) refuse to administer vitamin K intravenously due to the risk of anaphylaxis

• Historically, the product had castor oil…• Risk:

– 0.04-11/10,000 doses

1. Fiore et al. J Thromb Thrombolysis 2001; 11:175-83

Black box warning

• Widespread misconception that subcutaneous is better than oral despite clear evidence of inferiority– Survey of 52 anticoagulant clinics in the USA –

25% had never used oral vitamin K

• No orally available tablet in many countries (and often only 5 mg tablets)– Oral Vitamin K is available in USA in 5 mg tablets

1. Vanier et al. Can J Hosp Pharm 2006;59:125-35 2. Libby et al. Arch Intern Med 2002; 162: 1893-6.

Give intravenous formulations of Vitamin K orally

Is a secret you need to learn in training

3 situations where oral vitamin K should suffice

1. Asymptomatic high INRs– INR>8-10

2. Non-emergency surgery– Delay of 6 hours medically safe

3. Non-critical bleeding– Epistaxis, dental bleeding, hemorrhoidal

bleeding, vaginal bleeding without hemodynamic instability

Asymptomatic high INRs

• Clinical trials have not been performed to delineate when you need to intervene when faced with a high INR

• An INR between 5-9 is associated with a small but measureable increase in bleeding (0.95% per month)

1. Garcia et al. J Am Coll Cardiol 2006; 47: 804-8.

Asymptomatic high INRs

• Logistical issues– If you need to intervene in a country without

an appropriately dosed oral formulation, you need to send the patient to the emergency department to get oral vitamin K

Asymptomatic high INRs

Guideline INR Recommendation

Australian/N Zealand

>104.5-10 + high risk*

3-5 mg po/iv1-2 mg po or 0.5-1.0 iv

Am Coll Chest Surg >10 po (no dose specified)

British Committee SH

>8 1-5 mg po

*High risk: major bleed in last 4 weeks, major surgery in last 2 weeks, platelet count <50, liver disease or concurrent anti-platelet therapy

1. Tran et al. Med J Austral 2013; 198: 198-9.2. Holbrook et al. Chest 2012; 141: e152S-184S.3. Keeling et al. Br J Haematol 2011; 154:311-24.

Asymptomatic high INRs

There is consensus that you should NEVER give a blood product when faced with this

clinical problem

Non-emergency surgery

• Intravenous vitamin K is faster than all other routes of administration

• Studies confirm:– Oral is faster than placebo or nothing– Oral is faster than subcutaneous– Intravenous is faster than oral

1. Vanier et al. Can J Hosp Pharm 2006;59:125-35

Example from 1 report

1. Watson et al. Brit J Haematol 2001; 115:145-149.

IV vitamin K expedites time to OR

• 1 mg of vitamin K iv (vs. nothing) decreases time to OR (and INR<1.5) by 2 days

• 1 mg of vitamin K iv (vs. nothing) decreased time to OR (and INR<2) by 44 hours

1. Bhatia et al. Ann R Coll Surg Engl 2010; 92:473-476.2. Tharmarajah et al. J Orthop Trauma 2007; 21:26-30.

Concern re: warfarin resistance after vitamin K administration

• Patients with INR 5-10 administered 2 mg of oral vitamin K

• Warfarin resistance = inability to restore therapeutic INR after overcorrection from oral vitamin K (the mean of the next two INRs was below 1.5 after reinitiating warfarin therapy)

• 6 of 1611 (0.6%) were labelled “warfarin resistant” (all female)

1. Denas et al. J Thromb Thrombolysis 2009;27:340-7.

Non critical bleeding

• Examples:– Dental bleeding, epistaxis, hematuria,

hemorrhoidal bleeding, vaginal bleeding– First: determine if reversal is required

(sometimes topical tranexamic acid works)

• Guideline recommendations (note: no PCCs) Guideline Recommendation

Australian/N Zealand

1-2 mg po or 0.5-1.0 iv

Brit Committee SH 1-3 mg iv

Review

• Warfarin reversal for bleeding or procedure is a common clinical scenario

• Use blood products only for critical bleeding and emergency surgery in less than 6 hours

• Intravenous vitamin K is the fastest way to reverse an elevated INR (4-6 hours) in emergency settings and is safe

• INR over 8-10 use oral vitamin K• Urgent surgery use iv vitamin K (dose unclear)• Non-critical bleeding use low dose iv vitamin K

4. Don’t perform serial blood counts on clinically

stable patients

Inappropriate lab tests

• 20.6% (16.2, 24.9) of all tests • 25% (14.0, 36.1) of tests in USA • 33.3% (20.2, 46.3) of Hematology tests

– Includes many tests• 7.4% (2.5, 12.3) of repeat tests

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Zhi et al, PLoS ONE, 2013

Over-Testing Risks

• Money• Reaction to abnormal results• Phlebotomy risks

– Needle site pain– Hematomas– Nerve injury– Infection– Anemia

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Most Important Over-Testing Risks

• Reaction to abnormal results– Inappropriate Transfusions

• Phlebotomy Induced Anemia

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Predictors of AnemiaVariable Univariate Analyses Final Multivariate Analysis

Parameter Estimate (SE) P Value Parameter Estimate (SE) P Value

Volume of blood draw, mL 0.073 (0.012) <.0001 0.070 (0.011) <.0001

Age, y −0.069 (0.038) .0704 −0.8211 (0.036) .0247

Gender, male vs female 0.770 (1.266) .5432 * *

Length of hospitalization, days

0.468 (0.150) .0019 § §

Hemoglobin level on admission, g/L†

0.184 (0.033) <.0001 0.168 (0.032) <.0001

Intravascular volume depletion at admission‡

2.472 (1.255) .0496 2.615 (1.203) .0303

Chronic diseases that may cause anemia

0.833 (1.275) .5142 * *

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Thavendiranathan et al. 2005 J Gen Intern Med, 20(6): 520-4

Predicted Phlebotomy Effects

Volume of Blood Draw, mL Expected Change in Hemoglobin, g/L (95% CI)*

Expected Change in Hematocrit, % (95% CI)

Scenarios Resulting in the Volume of Blood Draw

10 0.7 (0.5 to 0.9) 0.19 (0.13 to 0.25) Routine labs (CBC, electrolytes, renal and coagulation profiles)

50 3.5 (2.4 to 4.6) 0.95 (0.65 to 1.25) Routine labs for 5 days

100 8.0 (4.8 to 10.2) 1.90 (1.30 to 2.50) Routine labs for 5 days, acute anemia workup, 3 sets of cardiac enzymes

200 14.0 (9.6 to 18.4) 3.80 (2.60 to 5.00) Routine labs for 10 days, 3 sets of cardiac enzymes, 3 sets of liver profile, transaminitis work-up

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Acute MI patients

• Study of 57 hospitals from 2001-2008• 20.1% developed moderate to severe

anemia (<11 g/dL)

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Arch Intern Med. 2011;171(18):1646-1653. doi:10.1001/archinternmed.2011.361

Tests Contributing to Diagnostic Blood Loss

Hospital Phlebotomy Variability

Date of download: 9/26/2014Arch Surg. 2011;146(5):524-527. doi:10.1001/archsurg.2011.103

Education Decreases Costs

Safe Reductions

• Vanderbilt University Study1. All orders beyond 72 hours appeared on

screens and decisions required. 1. Educational material on screens.

2. Most orders constrained to one time only.

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Date of download: 9/26/2014Ann Intern Med. 2004;141(3):196-204. doi:10.7326/0003-

4819-141-3-200408030-00008

Vanderbilt ExperienceTests Ordered

Tests Discontinued

Safety with Fewer Labs

Senior Physician Review & Education Reduces Tests

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Tests per admission per day

Before Intervention

Mt Sinai J Med 73(5): 787-794.

No change in Readmission Rates

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Service with intervention

CBCs and RBC Transfusions

• Stable patients should not be transfused based on lab values alone.

• If instability develops, CBC might be appropriate

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Platelet counts

• Platelet transfusion (trigger and dosing) studies based on morning platelet count.

• Provides safe transfusion strategy.• Diurnal variation

– Unclear what platelet transfusion trigger should be later in day

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Complete Blood Counts (CBCs)

• Perform if – Reasonable expectation of an abnormality– Treatment or diagnostic decisions to be made

based on abnormality

• Do not take autopilot approach of serial CBCs– Decrease costs– Decrease anemia– Safe

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5. Don’t transfuse O-negative blood except to O-negative patients and in

emergencies for women of child-bearing potential of unknown blood

group.

Why?

• Group O negative units are in short supply• The risk of anti-D formation is low and of

consequence only for women of child bearing potential

• Anti-D is picked up on antibody screen, is associated with severe hemolytic disease of the fetus and newborn, it is not associated with severe hemolytic transfusion reactions

O negative3.3%O positive

9.2%

Other87.5%

Demographics• 49.4% of the 13,785,000 RBC transfusions

were group O– 39.8% O positive and 9.6% O negative

• 45% of whites and 49% of African Americans are group O

• 16% of whites and 7% of African Americans are D negative– 7.2% of whites 3.4% of African Americans

are group O D negative• 87% of donors are white

Why is O neg use high?

• Massive transfusion

• Emergency release

• Inventory management

• Antigen negative

• Policies

– When to switch O neg patients

– What to use in an emergency

– After how many units to switch

MTP ExamplesStudy Package 1 Package 2 Package 3 CommentsDente et al. 6 RBC units

6 AB plasma units6 RBC units6 plasma units1 SDP unit

6 RBC units6 plasma units10 cryo units

rFVIIa upon request

Cotton et al.

10 RBC units4 AB plasma units2 SDP units

6 RBC units4 plasma units2 SDP units

Repeat package 2

Cryo upon request

O’Keeffe et al.

5 RBC units2 AB plasma units

5 RBC units2 plasma units1 SDP unit

5 RBC units2 plasma units10 cryo unitsrFVIIa

 

Nunez et al.

10 RBC units6 AB plasma units2 SDP units

Repeat package 1

Repeat package 1

 

Riskin et al. 6 RBC units4 plasma units1 SDP unit

Repeat package 1

Repeat package 1

rFVIIa considered

What are the risk of D positive RBCs to D negative recipients?

• Recent studies demonstrate about 20% anti-D formation rate

TRANSFUSION 2008;48:1318-1324.

Emergency release uncrossmatched units

480 out of 5623 received 5203 RBC U161 patients received 581 ER RBC (2.8%)

1.21 ER RBC (range 1-14)Survival 56%No acute transfusion rxn1/10 male developed anti-D

University of Maryland

1:12001:611

1:69441:3146

Mayo clinic

All of the following criteria were required for a diagnosis of DHTR or DSTR to be considered: 1) a new antibody identified in the patient’s

serum, 2) a positive DAT demonstrating the presence of

IgG, 3) an eluate from the patient’s RBCs

demonstrated the presence of the same antibody that was identified in the serum, and

4) antigen typing of the patient’s RBCs demonstrated mixed-field typing for the antigen toward which the antibody in the patient’s serum and in the eluate was directed.

AcknowledgementsGroup Effort

• Jeannie Callum, M.D. Univ. of Toronto• Mike Murphy, MD, Univ. of Oxford, UK• Jonathan H. Waters, M.D. Univ. of

Pittsburgh• Beth Shaz, MD, New York Blood Center

THANK YOU

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