98

3

3

13:3014:00

14:0014:10 Opening Remarks

14:1015:00

15:0015:50

15:5016:10 Coffee break

16:1017:00

17:0017:20 Discussion Closing

2009/12/17

1

2

1

2pharmacogenetic testing

3

p g g

3

4 K

5

4

5

WarfarinDVT

Key Words

Warfarin DVT

6

DVT: Deep Vein Thrombosis

5

2009/12/17

2

VTEDVTPE

VTE1. 2.

VTE1. warfarin2.

67: :: warfarin 4-5 mg/day

: Ciprofloxacin

WarfarinAF

Key Words

Warfarin

9

AF: ( Atrial Fibrillation)

Warfarin

Ciprofloxacin

warfarin

10

1. CiprofloxacinINR2. warfarinciprofloxacin

Antithrombotic Drugs

AMIacute ischemic syndromePE

12

2009/12/17

3

1. Venous thromboembolismVETDeep vein thrombosis DVTPulmonary embolismPE

Anticoagulant

13

Pulmonary embolismPE2. atrial fibrillation3. Acute coronary syndromeACS

Eur J Haematol. 2009;82:339-49.

1

Warfarin

2

14

Unfractionated heparinLow molecular weight heparinFondaparinux

15

(1)

Low molecular weight heparin

VTE

Unfractionated heparin

INR 2-316

g p

Fondaparinux

Warfarin

(2)VTE3VTE

>4

1

17

VTE3

2

(3) VTE

3

18

VTELMWH3-6Warfarin

4

2009/12/17

4

(4)

Orthopedic surgeries

warfarin LMWH fondaparinux 10

5

19

fondaparinux 10

35

20

(1)AF

CHAD2 Risk Scoring

21

2 2Warfarin Antiplatelets

TIA: transient ischemic attack()

(2)

Warfarin34

(Cardioversion)

22

http://www.nhlbi.nih.gov/

antiplatelets

Warfarin

23

(1)

mitral valve

WarfarinINR 2.5-3.5

1

24

aortic valve

WarfarinINR 2.0-3.0

2

2009/12/17

5

(2)Bioprosthetic valves

3INR2-33aspirin

3

25

warfarinaspirin

4

WarfarinKVitamin K antagonistVKAKIIVIIIXXproteins C and SR- and S- enantiomers

2-5 4 02C9

K

p-4502C9

99

K20-60

27

warfarin

2

1

3 Warfarin

3

4

5

2-5 mg/day

Warfarin

Day INR Dosing (mg)1 52 53

2009/12/17

6

warfarin

31Clinical Laboratory News 2009; 35: 6http://www.fda.gov/

VKORC1CYP2C9

Variant Allele Frequencies for VKORC1 and CYP2C9 in Different Populations

European American

African American

Asian

VKORC1 0 37 0 22 0 99

32

1639G>A 0.37 0.22 0.99

CYP2C9*2 0.14 0.02 0.00

CYP2C9*3 0.06 0.01 0.04

Thromb Haemost 2006; 4:473.Thromb Haemost 2007; 98:570.

warfarin: 5.1 mg/day: 3.1 mg/day

WarfarinINR

1-2

Warfarin

INR4

1

INR1-2

1

INR1

2

33

Warfarin

34

Heparinantithrombin

activated partial thromboplastin timeaTTP1.5-2.5

LMWHs

anti-XaQ12H

: 0.3-0.5 units/ml : 0.6-1.0 units/ml

QD: 1.0-1.5 unit/ml

35

LMWHs vs UFH LMWHs UFH

36

2009/12/17

7

1

2

38

2

3

www.clotcare.com

Warfarin

LMWH

39

anti-Xaor INR

1

2 warfarin

40

3

4

WarfarinVitamin K

1

41

2

3

Warfarin1

2 warfarin

42

5 warfrain

3

4

2009/12/17

8

44

1

2

45

3

4 INR

46

2009/12/17

1

1

Outline

2

3

Anticoagulant medication adverse events

MEDMARX data report 2001- 2006

20,661

17,262

13,98315,000

20,000

25,000 1 Heparin2 Warfarin

3 Enoxaparin

4

3,6171,581 1,526 462 294 230 197

0

5,000

10,000

N= 1,156,330

598,163 medication errors associated with

anticoagulant

MEDMARX data report 2001- 2006Severity of anticoagulant medication errors

54,273

40,000

50,000

60,000

5

3,319 1,724 -

10,000

20,000

30,000

Potential errors Non-harmful errors

Harmful or fatal errors

N= 59,316

Medication errors associated with anticoagulant therapy in the hospital

3.5 year period

Brigham and Womens hospital

AnticoagulantsNo. of

t (%)130

(7 2%)

6

Medication errors 1,809

Anticoagulation-related medication errors 130

events (%) (7.2%)Event

rate/10,000patient-days

1.72

Am J Cardiol 2004;94:532535

2009/12/17

2

Medication errors associated with anticoagulant therapy in the hospital

86

80

100

Distribution by medication

1 Unfractionated heparin

2 Warfarin

7 Am J Cardiol 2004;94:532535

27

123 3

0

20

40

60

unfractionatedheparin

warfarin lowmolecularweightheparin

argatroban lepirudin

N=130

2 Warfarin

3 Low-molecular-weight heparin

Medication errors associated with anticoagulant therapy in the hospital

Severity of anticoagulant medication errors

No deaths were attributed to any of the anticoagulant medication errors. 2 events (1 5%) that prolonged hospitalization

8 Am J Cardiol 2004;94:532535

2 events (1.5%) that prolonged hospitalization8 events (6.2%) that required medical interventionMany events required an increase in laboratory monitoring but caused no patient harm

Paying attention to anticoagulant medication errors

Medication Safety- NPSG.03.05.01Reduce the likelihood of patient harm

9

associated with the use of anticoagulation therapy.

New for 2008

Clarified and Revised for

2009

10

Managing anticoagulation patients in the hospital 2007

Establishing the inpatient anticoagulation service

Identification of the gaps

1

2

Monitoring and maintaining program

quality

6

5

11

Planning of the inpatient anticoagulation

Winning support for the inpatient anticoagulation

service

3

Pharmacist education and training

Patient education needs

4

Establishing the inpatient anticoagulation service ?

Identification of the gaps

Self-assessment items8 ke elements

1

12

8 key elementsGap analysis tool

FMEARCA

2009/12/17

3

Self-assessment items

1. Patient information (1-32)2. Drug information (33-66)3. Communication of drug orders and

other drug information (67-75)

8 key elements

13

4. Drug storage, stock, standardization, and distribution (76-87)

5. Medication device acquisition, use, and monitoring (88-98)

6. Competency and staff education7. Patient education (99-114)8. Quality processes and risk

management (115-125)

http://www.ismp.org/

Gap analysis toolWhen to use

Future(preventative)

Failure Mode and Effect Analysis

FMEARCAFishbone diagram

14

Retrospective(after the event or close call)

Root Cause Analysis

Institute for Safe Medication Practices 2007Managing anticoagulation patients in the hospital 2007

Establishing the inpatient anticoagulation service

Planning of the inpatient anticoagulation

Planning the changeTeam RAID analysis

!

2

15

yResult desired, Actions necessary, Indication to watch, Decision that remain

SWOT analysisStrengths, Weaknesses, Opportunities, Threat

Creating flowchart of the service designInput into patient care plan and chart documentation

Planning the changeThe members of the team

Anticoagulation program manager(team leader)Patient-centered pharmacists, who would be providing the service on a day-to-day basis

16

p g y yDirector of pharmacy technician (in case more distributive duties need to be handled by technician)Medical staff championNursing representative where the service will likely be heavily utilized

Creating flowchart of the service design

Pharmacist initial progress note1

17

Admit (1)

Creating flowchart of the service design

Anticoagulation Patient Profile2

18

2009/12/17

4

Creating flowchart of the service design

Heparin/Coumadin monitoring form 3

19

Establishing the inpatient anticoagulation service

Winning support for the inpatient anticoagulation service

!

3

Supporting justificationConsider reviewing the adverse drug events

20

Consider reviewing the adverse drug eventsCommunication essentials

Consensus guidelines for outpatient anticoagulation management

Pharmacy and therapeutics committee rolePolicies, procedure, consult forms, guidelines

Making proposal to administration

Adoption by a newly-planned inpatient coagulation service

Recombinant factor VIIa orders

21

Anticoagulation bridging guidelines

Guidelines for perioperative management of patients with noncardiac disease who receive oral anticoagulation

1

22

Guidelines for perioperative management of patients with cardiac disease who receive oral anticoagulation

2

Anticoagulation bridging guidelines

23

Warfarin discharge work checklistPatient going home

24

2009/12/17

5

Warfarin discharge work checklistPatient going to an Institutional setting

25

Heparin protocolClinical pharmacist guidelines

26

Establishing the inpatient anticoagulation service

Pharmacist education and trainingDesign of the education program

Educational techniquesPrecepting

4

Bloom level of cognitive learning

Appropriate instructional methods

27

KnowledgeReadingLecture

Comprehension Guided discussionsInteractive lecture

Application Case presentation Analysis Case-base teaching

Synthesis Simulation/role-playPractice- based teaching

Evaluation

Skills for inpatient anticoagulation pharmacists

28

Establishing the inpatient anticoagulation service

Patient education needs

Low health literacy evaluationOlder patients

5

29

Patients with limited educationPatient with limited English proficiencyPoor patientsMinority patients

Patient training check-off list: Warfarin

30

2009/12/17

6

Establishing the inpatient anticoagulation service

Monitoring and maintaining program quality

PlanPlanning the changes

6

31

Planning the changes Do

Implementing the changesStudy

Study the effects of changesAct

Act on the study results and repeat the cycle

Process quality audit for warfarin

32

33

Time line and progression of the anticoagulation pprogram

3434Jt Comm J Qual Patient Saf. 2008 ;34:196-200

Impact of anticoagulation program on number of adverse events per 1,000 doses dispensed

3535 Jt Comm J Qual Patient Saf. 2008 ;34:196-200

Cost-benefit evaluation The differences in anticoagulant adverse event rates between 2004 and 2006 t l i f

36

2006 suggest an annual savings of up to $9.8 million in avoidable costs.

Jt Comm J Qual Patient Saf. 2008 ;34:196-200

2009/12/17

7

Enoxaparin DUE

96 enoxaparin

37

11%ADE7%

Enoxaparin enoxaparinClcr30 ml/min

38

enoxaparinEnoxaparin

Enoxaparin

39

warfarin acetylsalicylic acid

40

41

42

2009/12/17

8

Conclusion

43 44

Massachusetts College of Pharmacy (B.S)

The Ohio State University (Pharm. D)

2009/12/17

1

1

2009/12/17

OutlineOverview the Formation of Thrombosis

Review the History of Anticoagulants

Discuss the challenges and limitations associated with VKA therapy

2

py

A New Era of Anticoagulation

Conclusion

Better Oral Anticoagulation: New Agents or Better Management Method?

Thrombosis Formation

3

ThrombosisThe process through which a fibrin clot is formed via activation of plateletsplatelets and the clotting cascadeclotting cascade

4

Types of Thrombosis

ArterialArterial VenousVenousPlatelet-based (white) thrombusPlatelet-based (white) thrombus Fibrin-based (red) thrombusFibrin-based (red) thrombus

Platelet-VWF Coagulation factors

5

Platelet-VWF interactions critical

Associated with end-stage atherosclerosis

Coagulation factors critical

Venous stasis

VWF: von Willebrand factor

Antithrombotic Agents

Prevention and Rx of thrombosis in the venous and arterial systems

Only for arterial or intracardiac thrombosis as these thrombi are rich in platelets

6

Used for the acute Rx of thrombosis (i.e., AMI, AIS and massive PE)

2009/12/17

2

Coagulation is initiated by the extrinsic pathway and amplified by thrombin through the intrinsic pathway

7

Anticoagulation: Who and When (1)

PE

Venous thromboembolism

DVT

Prosthetic

Arterial thromboembolism

AF/Flutter

8

Primary Rx and prophylaxis

mechanical valves

Severe CHF

Primary Rx and prophylaxis

Pulmonary hypertension

Anticoagulation: Who and When (2)

Non-ST elevated MI

Acute coronary syndromes

Unstable Angina

9

Non ST elevated MI

ST-elevated MI

Secondary prevention

History of Anticoagulants

10

Historical Development of Anticoagulants

1930s 1940s 1980s 1990s 2000s

2008Class

Target

Heparin VKA LMWHDirect

Thrombin Inhibitor

Indirect Xa Inhibitor

ATIII+Xa+IIa

(1:1 ratio)

II+VII+ IX+X+

Protein C/S

ATIII+Xa+IIa

(Xa>IIa)

ThrombinATIII+Xa Oral Direct

Factor Xa Inhibitors

Route

11

Parenteral ParenteralOral Parenteral Parenteral

Increasing specificity

IIa Xa

Pareteral Oral

For the past decades, anticoagulants are

HeparinsUnfractionated Heparin (UFH)

Low Molecular Weight Heparin (LMWH)

VKAsAcenocoumarol (Sintrom)

Warfarin (Coumadin)

Fluindione (Previscan)

Phenoprocoumon (Marcoumar)

12

Phenoprocoumon (Marcoumar)

IIVIIIXX

Vitamin K -carboxylation

2009/12/17

3

The Only Licensed Oral Anticogulants-VKAs

Warfarin is th t

13

the most used agent

http://www.dadebehring.com/education/hemostasis/figure4.htm

Why Do We Need New Anticoagulants?

Current anticoagulation therapies are

14

suboptimal!

The challenges and limitations associated with VKA therapy

15

Vitamin K antagonists Are Effective

Stroke prevention Stroke prevention inin ptpts with s with AFAF

Prevention of thromboembolism in pts with artificial heart valves

Chronic

16

Secondary prevention of venous thromboembolism

primary prevention of venous thromboembolism

Chronic Indication

Warfarin Therapy Is Problematic

2 Narrow therapeutic windowmonitoring and dosage adjustments

1Mode of action: slow, indirect, and not targeted

17

3 Common genetic polymorphisms affect warfarin dose requirements

4 Lots of food- and drug-drug interactions

5 Inconvenience for patients and physician underuse

Narrow Therapeutic Window

Warfarin thrombosisWarfarin bleeding

s Narrow

18

Dose

Thro

mbo

sis

Ble

edin

gNarrow therapeutic window

Ansell et al., Chest 2004; Hirsh et al., Chest 2004

Hylek EM, et al. N Engl J Med 1996;335:540-546.

2009/12/17

4

Warfarin Therapy

19

ClottingBleeding

A New Era of AnticoagulationFactor Xa (FXa) vs.

Direct Thrombin Inhibitors (DTI)

20

Conventional Anticoagulant : Multi-target

LMWH

Warfarin IX XII VIITF/VIIa

IXa

VIIIaIIa Antithrombin III +Indirectly

Proteins C and S+

+ Xa

21

Fondaparinux

XIa

XIIaAntithrombin III + Xa

EmergingSingle-target

Xa IIa

The Critical Target of Coagulation Waterfall

Targets For New Anticoagulants

TF/VIIa

X IX

IXaVIIIa

TFPI (tifacogin)

APC (drotrecogin alfa)sTM (ART-123)

TTP889

22

XimelagatranDabigatran

RivaroxabanApixabanLY517717YM150DU-176bPRT-054021

Xa

IIa

VIIIa

Va

II

FibrinFibrinogen

FondaparinuxIdraparinux (biotinylated)

DX-9065aOtamixaban

AT

sTM (ART 123)

Adapted from Weitz & Bates, J Thromb Haemost 2005

Xa

IIa HirudinBivalirudin

Thrombin

Properties of an Ideal AnticoagulantProperties Benefits

Orally active

Rapid onset of action

No food or drug interactions

Ease of administration

overlap with a parenteral agents

Simplified dosing

23

Predictable anticoagulant effect

Extra-renal clearance

Rapid offset of action

Safe antidote

Favorable net clinical benefit

No routine coagulation monitoring

Safe in pts with renal insufficiency

Simplifies management in case of bleed or need for intervention

Useful in case of major bleed

Rx benefit outweighs risk

Comparison of Three Upcoming Novel Oral Anticoagulants- in phase III clinical trials

24SWISS MED WKLY 2009:139:60-64.

2009/12/17

5

What About Thrombin as a Target?Lessons Learned from Ximelagatran

Ximelagatran

it i i d d

25

Thrombin is a viable target

can be given in orally, fixed doses without routine coagulation monitoring

monitoring is needed to ensure no off-target ADRs

Dabigatran: Oral Prophylaxis forVenous Thromboembolism

European Medicines Agency granted marketing authorization on March 18, 2008 In Canada, approval came on June 13, 2008.

The prodrug dabigatran etexilate is

26

p g gconverted completely to active dabigatran

Clinical Trial Outcomes

27Eriksson BI et al. Lancet 2007; 370:94956. Eriksson B. American Society of Hematology 48th Annual Meeting; December 11, 2006; Orlando, FL.

Caprini JA et al. 2007 Congress of the International Society on Thrombosis and Hemostasis; July 7-13, 2007; Geneva, Switzerland.

Thrombin Has Many Functions, in Addition to Being a Procoagulant

ProcoagulantFibrin clot and platelet plugFeedback activation of coagulationClot stabilization

AnticoagulantProtein C activationProstacyclin formation

Thrombin

28

Cellular proliferationDirect mitogen for fibroblasts PDGF and TGF- from plateletsPDGF formation in endothelium

InflammationP-selectin expressionNeutrophilmonocyte adhesionChemotactic for PMNsEndothelial PAF formation

PAF = Platelet-activating factor; PDGF = Platelet-derived growth factor; PMN = Polymorphonuclear leukocyte; TGF = Transforming growth factor. Esmon CT. Presented at ISTH 2005.

The only known functions of FXa are either procoagulant or proinflammatory

FXa May Be A Better Target Than Thrombin

Has few functions outside coagulationHas few functions outside coagulation

Thrombin inhibitors are associated with rebound thrombin generation no evidence with FXa inhibitors

Thrombin inhibitors are associated with rebound thrombin generation no evidence with FXa inhibitors

29

FXaFXa

Efficacy of heparin-based anticogulants improves as selectivity for FXa

Efficacy of heparin-based anticogulants improves as selectivity for FXa

Has wider therapeutic window than thrombinHas wider therapeutic window than thrombin

Types of Factor Xa Inhibitors

30

2009/12/17

6

Direct Factor Xa Inhibitors

FX i th

FXa

DirectFXa inhibitors

eg Rivaroxaban

31

FXa in the prothrombinase

complex

Direct Factor Xa inhibitors can inhibit Factor Xa within the prothrombinase complex

Clinical Development of Oral Factor Xa Inhibitors

32

the first oral direct FXa inhibitor

European Heart Journal 2007;29:155-165

In September 2008, it granted by Health Canada and the European Commission for marketing authorization

Phase II Phase III

VTE prevention after major orthopaedic surgery

ODIXa-HIP1 ODIXa-HIP2ODIXa-KNEEODIXa-OD-HIP

RECORD1 RECORD2RECORD3 RECORD4

Clinical Programme Overview of Rivaroxaban

33

VTE prevention in hospitalized medically ill patients

VTE treatment ODIXa-DVTEINSTEIN-DVT EINSTEIN-DVT

EINSTEIN-PEEINSTEIN-EXT

Stroke prevention in atrial fibrillation

Secondary prevention of acute coronary syndromes

Comparison of the RECORD Trials (Phase III)Trials for Trials for VTE ProphylaxisVTE Prophylaxis

Rivaroxaban 10 mg qd investigatedSame study design and efficacy and safety outcomes

Randomized, active-comparator-controlled, parallel-group,double-blind, double-dummy

Same independent, blinded adjudication committees

34

KNEE replacementRivaroxaban 10 mg od

for 1014 daysvs

enoxaparin 40 mg odfor 1014 days

N=2,531

HIP replacementRivaroxaban 10 mg od

for 5 weeksvs

enoxaparin 40 mg od for 5 weeks

N=4,541

HIP replacementRivaroxaban 10 mg od

for 5 weeks vs

enoxaparin 40 mg odfor 1014 days then

oral placeboN=2,509

KNEE replacementRivaroxaban 10 mg od

for 1014 daysvs

enoxaparin 30 mg bid for 1014 days

N=3,148

RECORD Trials Outcomes (1)

35

Cardiol Rev. 2009;17:192-7

RECORD Trials Outcomes (2)

36

Cardiol Rev. 2009;17:192-7

2009/12/17

7

Major VTE across the RECORD program

37

Cardiol Rev. 2009;17:192-7

Symptomatic VTE across the RECORD program

38

Cardiol Rev. 2009;17:192-7

Major bleeding across the RECORD program

39

Cardiol Rev. 2009;17:192-7

RECORD Programme

1 Superior VTE prevention vs enoxaparin

Extended prophylaxis with rivaroxaban regimen superior to short-term prophylaxis with enoxaparin regimen after THR

40

3 Reduced symptomatic

4 Similar safety profile to enoxaparin

ODIXa-DVT & EINSTEIN-DVT StudyPhase III Trials for Trials for VTE TreatmentVTE Treatment

41Cardiol Rev. 2009;17:192-7

Limitations of the Clinical Trials

Absence of a dose-dependent relationship in the prevention of VTE and major bleeding

42

So far have only shown the prophylactic benefits of rivaroxaban in elective knee and hip arthroplasty

2009/12/17

8

Features of Apixaban

Direct, selective inhibitor of Factor Xa with high oral bioavailability

Concentration-dependent anticoagulation; Effective in preclinical models of venous and arterial thrombosis

43

No reactive intermediates, no food effect; t1/2 ~ 12 hrs

Low likelihood of drug interaction; multiple pathways of elimination

He et al., ASH, 2006, Lassen, et al ASH, 2006

26.625

30

Apixaban qd and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patients

t t

Total VTE and AllTotal VTE and All--Cause Cause Mortality (%)Mortality (%) Major Bleeding (%)

25

30

Apixaban for Prevention of VTE After Major Orthopaedic Surgery (phase II APROPOS)

Apixaban treatment groups had lower Apixaban was associated

44

Lassen et al. Blood 2006

10.68.6 6.8

15.6

0

5

10

15

20

25

Enoxaparin(30mg bid)

20mgApixaban Apixaban

(Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin (INR

1.8-3.0)

Enoxaparin(30mg bid)

20mgApixaban Apixaban

(Total Daily Dose)(Total Daily Dose)

10mg5mg Warfarin (INR

1.8-3.0)

Perc

ent

Perc

ent

1.3 1.63.0

0 00

5

10

15

20

25p g pprimary efficacy event rates than the comparators enoxaparin or warfarin.

pwith a significant in total bleeding events independent of treatment regime

Apixaban for the Treatment of DVT: The Botticelli-DVT Study

Apixaban bid (5 and 10mg) and qd (20mg) were assessed relative to LMWH or fondaparinux followed by VKA, in 520 pts

10

Composite of Symptomatic Composite of Symptomatic Recurrent VTE and Deterioration of Recurrent VTE and Deterioration of

Thrombotic Burden (%)Thrombotic Burden (%)Major Bleeding (%)Major Bleeding (%)

10

All th d f i b

45

Bller, Eur Heart J 2006

0.80

0.80

0

2

4

6

8

20mg qd

Apixaban Apixaban

10mg bid

5mg bid

LMWH/ fondaparinux

+ VKA

Perc

ent

6.0 5.6

2.6

4.2

0

2

4

6

8

20mg qd

Apixaban Apixaban

10mg bid

5mg bid

LMWH/ fondaparinux

+ VKA

Perc

ent

All three doses of apixaban were considered similar to standard of care

Apixaban : Phase III

Advance 1,2,3 orthopaedic surgeryAdopt medically illAppraise 2 - ACS

46

Aristotle - atrial fibrillation

Better Oral Anticoagulation: New Agents or Better Management Method?

47

Management Method?

Considerations

New agents are nonNew agents are non--inferior to inferior to conventional VKA therapy as it conventional VKA therapy as it

tl i dtl i d

48

currently is managedcurrently is managed

2009/12/17

9

Selected Potential Problems with the New Agents

2 No antidote

1Potential, not-yet-recognized adverse effects

49

3 No test for dosage adjustment, assessing adherence, or evaluating interactions

4 Pharmacokinetic considerations

Conclusion

50

22 A significant unmet need for a convenient, predictable anticoagulant that is both effective and safe for the prevention and Rx of thromboembolic disorders

11VKAs are still widely used oral anticoagulants

33 Several novel oral anticoagulants have recently demonstrated efficacy and safety in Phase III trials

51

55 New oral anticoagulants offer the advantage of convenient oral administration and no required laboratory monitoring or frequent dose adjustments

demonstrated efficacy and safety in Phase III trials

44 The limitations of these trials should be considered when trying to apply results to general clinical practice

Thank You!

52

2010-2011 Bimonthly Clinical Pharmacy Symposium

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