The Aprotinin Controversy: Oh The Aprotinin Controversy: Oh my –what next?my –what next?

Bruce D. Spiess, MD, FAHABruce D. Spiess, MD, FAHAProfessor of Anesthesiology and Emergency MedicineProfessor of Anesthesiology and Emergency Medicine

Director VCURESDirector VCURESRichmond, VirginiaRichmond, Virginia

DisclosuresDisclosures Bayer PharmaceuticalsBayer Pharmaceuticals Synthetic Blood InternationalSynthetic Blood International The Medicines CompanyThe Medicines Company McSPI Hematology Sub-Group McSPI Hematology Sub-Group

Director (Past)Director (Past)

Some drug studies quoted were Some drug studies quoted were done “off label”.done “off label”.

CPB: The Ultimate in “Biologic CPB: The Ultimate in “Biologic Complexity”Complexity”

The insult of CPB:The insult of CPB: HeparinHeparin Contact ActivationContact Activation HeatingHeating

Leukocytes and PlateletsLeukocytes and Platelets

Complement SystemComplement System

Coagulation SystemCoagulation System

Kinin GenerationKinin Generation

Fibrinolytic SystemFibrinolytic System

Protease Activated Protease Activated

ReceptorsReceptors

Kallikrein

Kallikrein

Neutrophils

inflammatory mediatorsinflammatory mediators

(IL-1, IL-6, elastase)(IL-1, IL-6, elastase)

Factor XII

HMWK

Bradykinin

Complement inflammationinflammation

vasodilationvasodilation

vascular permeabilityvascular permeability

t-PA releaset-PA release

Plasminogen Plasmin

phagocytosisphagocytosis

Contact Activation Build Slide

fibrinolysis

enzymesfree radicalsaa metabolitesinterleukins

activation aggregation consumptioncoagulation

kinin generation vasodilatationvascular permeability

pressor response

XI

XIa

XIIPrekallikrein

HMWK

XIIa

neutrophils

TF VII

C3

TFPI

plateletsFibrin (p)

Fibrin (cl)

D-dimer

Fibrin (m)

XIIIXIIIa

Fibrinogen

endotheliumBradykinin

Prorenin

Renin

Plasminogen

uPAtPA

Protein C

VIIIaVIII

V Va

Tissue Factor

Complex (TF:VIIa)X IXa

IX

Xa

Prothrombin

C5b-9

C4b2a C1 Heparin-Protamine Complex

ComplementC3b C5b

C5b67

C3a

5

Structure of Aprotinin

Lysine

Lysine

Data on File: Bayer Pharmaceuticals Corporation

AprotininAprotinin

A Serine Protease InhibitorA Serine Protease Inhibitor

Binds with the human serine proteases:Binds with the human serine proteases:

TrypsinTrypsinPlasminPlasminPlasma kallikreinPlasma kallikreinTissue kallikreinTissue kallikreinElastaseElastaseUrokinaseUrokinase

decreasing decreasing affinityaffinity

Fritz H & Wunderer G, Fritz H & Wunderer G, Drug ResearchDrug Research, 1983;33(1):479-494, 1983;33(1):479-494

Aprotinin Dose-Response Aprotinin Dose-Response Red Cell TransfusionRed Cell Transfusion

0

2

4

6

Mea

n R

ed C

ell

Tra

nsfu

sion

(U

nit)

0 420 840 1260

Total Aprotinin Dose (mg)

Cardiac SurgeryPlacebo

200 mL prime

100ml Load + 100mL Prime + 25mL/hr

200ml Load + 200mL Prime + 50mL/hr

Royston Ann Thorac Surg 1998;65(4):S9-19

Orthopaedic SurgeryPlacebo 200 mL Load + 50 mL/hr400 mL Load + 100 mL/hr

Samama et al Anesth Analg 2002;95:287-93

3.5

8

0.8

4.1

0

3

6

9

Bidstrup Murkin

1393

352

2766

1410

0

1000

2000

3000

Aprotinin Use in Aspirin-Pretreated Patients

Aprotinin Use in Aspirin-Pretreated Patients

Bidstrup Murkin

Bidstrup et al. Perfusion 1990;5:77Murkin et al. J Thorac Cardiovasc Surg 1994;107:554

p < .001p < .001

AprotininControlControl

Thoracic Drainage (ml) Total Units Transfused(Blood Products)

50%

78%

n = 25

p = N/A

n = 25n = 18n = 18 n = 26 n = 26n = 29 n = 29

1200

760

0

200

400

600

800

1000

1200

1400

Aprotinin in Primary CABG Patients on Clopidogrel

Aprotinin in Primary CABG Patients on Clopidogrel

van der Linden J et al. Circulation 2005;112:I276

Control

Aprotinin

p < .001

Blood Loss (ml)

n = 38 n = 37

2.8

1.2

0.9

0.1

0

1

2

3

4

5

Un

its T

ran

sfu

sed

Platelets

RBC

Control Aprotinin

p = .002

n = 38 n = 37p = .02

1 Unit = 500 mlplatelets

Blood Products Transfused

AprotininAprotinin

Efficacy- >7400 articles

Safety- Is that enough?Is a drug that decreases

bleeding pro-thrombotic?Other Drugs-EACA, TA

Aprotinin for Off-Pump CABGAprotinin for Off-Pump CABG

Poston RS et al. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery Poston RS et al. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting. AnnThorac Surg.2006;81:104-11.bypass grafting. AnnThorac Surg.2006;81:104-11.

Jeremiah Brown PhDJeremiah Brown PhD

Many on the committee were conflicted Many on the committee were conflicted regarding aprotinin.regarding aprotinin.

Meta-analysis X 2Meta-analysis X 2NEJM 2006;354:1953-7.NEJM 2006;354:1953-7.Circulation 2007;115:2801-13.Circulation 2007;115:2801-13.

Copyright ©2007 American Heart Association

Brown, J. R. et al. Circulation 2007;115:2801-2813

Adverse outcomes by antifibrinolytic agents: head-to-head comparison

Copyright ©2007 American Heart Association

Brown, J. R. et al. Circulation 2007;115:2801-2813

Renal failure and dysfunction by antifibrinolytic agent compared with placebo

Anti-FibrinolyticsAnti-Fibrinolytics

Mangano DT, Tudor JC, Dietzel C. The risk associated with aprotinin in Mangano DT, Tudor JC, Dietzel C. The risk associated with aprotinin in cardiac surgery. cardiac surgery. N Engl J MedN Engl J Med 2006; 354 :353-65. 2006; 354 :353-65.

The “First” ArticleThe “First” Article

4373 patients, observational, 4373 patients, observational, retrospective analysis of data retrospective analysis of data basebase

Increased renal failure, Increased renal failure, adverse cardiac outcomes, adverse cardiac outcomes, increased stroke or increased stroke or encephelopathy!encephelopathy!

Do you believe the data/analysis/statistics?

Channeling? Does this trump everything???

Mangano DT, Tudor IC, Dietzel CT and McSPI Mangano DT, Tudor IC, Dietzel CT and McSPI Investigators. The risk associated with aprotinin in Investigators. The risk associated with aprotinin in cardiac surgery. NEJM 2006;354:353-365.cardiac surgery. NEJM 2006;354:353-365.

The “Other Article”The “Other Article” 449 propensity matched patients for aprotinin v. TA out of a data base of 10,870 (TA 449 propensity matched patients for aprotinin v. TA out of a data base of 10,870 (TA

for the rest).for the rest).

Adverse events rates were comparable in the two groups, except for renal dysfunction (defined as a greater than 50% increase in creatinine concentration during the first postoperative week to >100 µmol/L in women and >110 µmol/L in men or a new requirement for dialysis support), which occurred in 24 percent (107/449) of aprotinin patients and 17 percent (75/449) of tranexamic acid patients (p = 0.01).

Keyvan Karkouti, W. Scott Beattie, Kathleen M. Dattilo, Stuart A. McCluskey, Mohammed Keyvan Karkouti, W. Scott Beattie, Kathleen M. Dattilo, Stuart A. McCluskey, Mohammed Ghannam, Ahmed Hamdy, Duminda N. Wijeysundera, Ludwik Fedorko, Terrence M. Yau (2006) Ghannam, Ahmed Hamdy, Duminda N. Wijeysundera, Ludwik Fedorko, Terrence M. Yau (2006) A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery risk cardiac surgery Transfusion 46 (3) , 327–338 Transfusion 46 (3) , 327–338

ChannelingChanneling

Physicians pick the drug that fits the risks Physicians pick the drug that fits the risks of the patient. of the patient.

Those with more risk received aprotinin Those with more risk received aprotinin (67 covariates positive).(67 covariates positive).

Can statistics (multi-variate/propensity) smooth all these biases out and reverse the effects of channeling?

FDA Cardio-Renal Meeting # 1FDA Cardio-Renal Meeting # 1

Karkhouti and Mangango PresentedKarkhouti and Mangango PresentedFDA votes: FDA votes: Restrict aprotinin to bypass

available only due to anaphylaxis.No change in warnings and no change in No change in warnings and no change in

marketing.marketing.Bayer complimented for transparency and Bayer complimented for transparency and

suggested that there should be expanded suggested that there should be expanded indications.indications.

Out of Left field!Out of Left field!

I3- “Study” revealed 3 weeks after the first I3- “Study” revealed 3 weeks after the first FDA meeting.FDA meeting.

What was the I3 “study”?What was the I3 “study”?Why was it not revealed –public Why was it not revealed –public

comment?comment?What is the real truth?What is the real truth?Bad-Bad PR!Bad-Bad PR!

Paper # 2Paper # 2

A Lot has Happened: Since we last A Lot has Happened: Since we last spoke!spoke!

Mangano Publications: JAMA, NEJMMangano Publications: JAMA, NEJM I3 (unpublished but reported to FDA)I3 (unpublished but reported to FDA)FDA-Cardio-Renal Advisory Committee FDA-Cardio-Renal Advisory Committee

MeetingMeetingSTS/SCA- GuidelinesSTS/SCA- GuidelinesFurnary, et al. paperFurnary, et al. paperOther-published work coming out dailyOther-published work coming out daily

What are your “Facts”?What are your “Facts”?What have you heard?What have you heard?

What is the truth!What is the truth! I3 study supported and proved the McSPI I3 study supported and proved the McSPI

data regarding mortality and renal failure?data regarding mortality and renal failure?FDA reviewed McSPI’s data and noted it FDA reviewed McSPI’s data and noted it

was the right analysis?was the right analysis?BART Study found significant more BART Study found significant more

mortality with aprotinin?mortality with aprotinin?The FDA forced the Bayer to withdraw The FDA forced the Bayer to withdraw

aprotinin from the market?aprotinin from the market?Aprotinin is no longer on the market?Aprotinin is no longer on the market?

The TruthThe Truth I3 was discredited as being highly confounded. Robust I3 was discredited as being highly confounded. Robust

( a lot of patients but Medicare and billing database)( a lot of patients but Medicare and billing database) FDA supported some of McSPI’s data but had major FDA supported some of McSPI’s data but had major

questions about some analysis.questions about some analysis. BART was stopped by the DSMB due to a non-BART was stopped by the DSMB due to a non-

significant (0.06) but strong trend towards more mortality significant (0.06) but strong trend towards more mortality with aprotinin. There was a problem with sever with aprotinin. There was a problem with sever hemorrhage leading to mortality. No final word yet!hemorrhage leading to mortality. No final word yet!

Bayer, notified the FDA of a hold on marketing of Bayer, notified the FDA of a hold on marketing of aprotinin.aprotinin.

Aprotinin is still produced, available but not actively Aprotinin is still produced, available but not actively marketed.marketed.

FDA MeetingFDA Meeting

www.FDA.govwww.FDA.gov (aprotinin, slides are (aprotinin, slides are available and you can available and you can (soon) get full (soon) get full transcript of meeting)- transcript of meeting)- see for yourself.see for yourself.

FDA Cardio Renal Meeting-9-12-07FDA Cardio Renal Meeting-9-12-07

Should aprotinin stay on the market: 17 yes, 1 abstain, 1 no

Should there be a label change to reflect data from the retrospective studies:16 no, 1 abstain

Should Bayer do a new (contemporary) study of aprotinin?17 yes, 0 no, 0 abstain

Did he get all the confounders Did he get all the confounders correct?correct?

That is the big question is it not?That is the big question is it not?Karkhouti did! As he added in each Karkhouti did! As he added in each

potential confounder the odds ratio for potential confounder the odds ratio for aprotinin decreased.aprotinin decreased.

His conclusion to the FDA was that only renal dysfunction existed as a real finding.

A partial retraction of his original paper?

At the end of the day!At the end of the day!

I3 –incomplete data set from a “billing I3 –incomplete data set from a “billing registry”, no independent inspection (cross registry”, no independent inspection (cross check) of original data, lacking many check) of original data, lacking many standard confounders.standard confounders.

McSPI articles-tremendously confounded McSPI articles-tremendously confounded and inconclusive-what you look at is what and inconclusive-what you look at is what you get!you get!

““If there is smoke is there fire?”If there is smoke is there fire?” Is it all due to transfusion?

Other papers by Mangano and McSPI that relate Other papers by Mangano and McSPI that relate to aprotinin, renal dysfunction, and Tx.to aprotinin, renal dysfunction, and Tx.

Moehnle P et al. Morbid risks of unnecessary red blood cell transfusion in stable Moehnle P et al. Morbid risks of unnecessary red blood cell transfusion in stable coronary artery bypass graft patients. coronary artery bypass graft patients. BloodBlood (American Society of Hematology (American Society of Hematology Abstracts) 2005; 106; abstract 427.Abstracts) 2005; 106; abstract 427.

Snyder-Ramos S et al. Snyder-Ramos S et al. On going variability in transfusion practices in cardiac On going variability in transfusion practices in cardiac surgery despite established guidelines. surgery despite established guidelines. BloodBlood (American Society of Hematology (American Society of Hematology Abstracts) 2005; 106:abstract 947.Abstracts) 2005; 106:abstract 947.

Kullier A et al. Impact of preoperative anemia on outcome in patients undergoing Kullier A et al. Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery. coronary artery bypass graft surgery. Circulation Circulation 2007; 116:471-479.2007; 116:471-479.

Aronson S et al. Risk index for perioperative renal dysfunction/failure: Aronson S et al. Risk index for perioperative renal dysfunction/failure: critical dependence on pulse pressure hypertension. critical dependence on pulse pressure hypertension. CirculationCirculation 2007;115: 733-42.2007;115: 733-42.

Ott E et al. Coronary artery bypass graft surgery--care globalization: the Ott E et al. Coronary artery bypass graft surgery--care globalization: the impact of national care on fatal and nonfatal outcome. impact of national care on fatal and nonfatal outcome. J Thorac J Thorac Cardiovasc SurgCardiovasc Surg 2007; 133: 1242-51. 2007; 133: 1242-51.

Ott E et al. Coronary artery bypass graft surgery--care globalization: Ott E et al. Coronary artery bypass graft surgery--care globalization: the impact of national care on fatal and nonfatal outcome. the impact of national care on fatal and nonfatal outcome. J Thorac J Thorac

Cardiovasc SurgCardiovasc Surg 2007; 133: 1242-51. 2007; 133: 1242-51.

Dramatic differences in aprotinin use: Dramatic differences in aprotinin use: Germany 69%, Canada 5.7%Germany 69%, Canada 5.7%

Dramatic differences in FFP usage: 10.6% Dramatic differences in FFP usage: 10.6% Germany, 1.4% CanadaGermany, 1.4% Canada

Dramatic differences in renal Dramatic differences in renal dysfunction/failure: More patients dialyzed dysfunction/failure: More patients dialyzed in Germany than had renal dysfunction???in Germany than had renal dysfunction???

What about TransfusionWhat about Transfusion Is transfusion an outcome or a risk, both?Is transfusion an outcome or a risk, both? In the year after McSPI’s first article there was a

14.7% sudden unprecedented increase in transfusion for heart surgery from the STS database..

Prior three years transfusion was stable even Prior three years transfusion was stable even though patient acuity had risen.though patient acuity had risen.

No data yet for transfusion or mortality after the No data yet for transfusion or mortality after the BART DSMB action.BART DSMB action.

What is the definition of human experimentation?

Niv Ad Propensity Matched Niv Ad Propensity Matched SurvivalSurvival

Propensity Matched for Aprotinin (yes/no)

0 1 2 3 4 5 6 70

25

50

75

100

No AprotininAprotininp<0.014

Year 0 1 2 3 4 5

No Aprotinin 554 541 539 536 527 432

Aprotinin 554 533 525 516 507 269

No. of Patients at Risk of Dying

Survival Time

Per

cen

t su

rviv

al

Niv Ad, Survival with and without Niv Ad, Survival with and without Tx. added into the analysis!Tx. added into the analysis!

All Patients

0 1 2 3 4 5 6 70

20

40

60

80

100

Aprotinin No, BP NoAprotinin No, BP YesAprotinin Yes, BP No

Aprotinin Yes, BP Yes

Survival Time

Perc

ent s

urvi

val

Propensity Matched for Aprotinin Use (yes/no)

0 1 2 3 4 5 6 70

20

40

60

80

100

Aprotinin No, BP NoAprotinin No, BP YesAprotinin Yes, BP No

Aprotinin Yes, BP Yes

Survival Time

Perc

ent s

urvi

val

The Right Analysis?The Right Analysis?

It is all about what you include!It is all about what you include!

Furnary Analysis 3-Ways!Furnary Analysis 3-Ways!

Tx. Causes Renal Failure!Tx. Causes Renal Failure!

The LatestThe Latest

8548 Pts at Munich Heart Center8548 Pts at Munich Heart Center Various dosages of aprotininVarious dosages of aprotinin Renal failure (dialysis)Renal failure (dialysis) Renal dysfunction (increased creatinine)Renal dysfunction (increased creatinine) No evidence of increased renal failure or No evidence of increased renal failure or

dysfunction even with increased dosing,dysfunction even with increased dosing, Risk factors (patient and operative) were related Risk factors (patient and operative) were related

to outcome.to outcome.

Dietrich W, Busley R, Boulesteix A-L. Effects of aprotinin dosage on renal function. Anesthesiology; 2008:189-98.

Brand New!Brand New! 9875 pts retrospective observational study9875 pts retrospective observational study Renal dysfunction without ACE OR 1.81(95% CI 0.79-Renal dysfunction without ACE OR 1.81(95% CI 0.79-

4.13 p=0.16)4.13 p=0.16) Renal dysfunction with ACE on bypass 1.73 (0.56-5.32, Renal dysfunction with ACE on bypass 1.73 (0.56-5.32,

p=0.34)p=0.34) 848 pts off pump with ACE 2.87 (1.25-6.58,p=0.013)848 pts off pump with ACE 2.87 (1.25-6.58,p=0.013) “ “ Our results have shown that aprotinin seems to be safe Our results have shown that aprotinin seems to be safe

during on-pump cardiac surgery.”during on-pump cardiac surgery.” Mouton R et al. effect of aprotinin on renal dysfunction in

patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet 2008;371:475-482.

The Duke PaperThe Duke Paper 10,275 pts over 10 years (1996-2005)10,275 pts over 10 years (1996-2005) 1343 (13.2%) aprotinin1343 (13.2%) aprotinin 6776 (66.8%) EACA6776 (66.8%) EACA 2029 (20.0%) no Rx.2029 (20.0%) no Rx. Creatinine Increase p<0.001 Dialysis: P=0.56 Mortality: 1.32 (95% CI 1.12-1.55) placebo

1.27 (95% CI 1.10-1.46) EACA

JCTVS March 2008JCTVS March 2008 “These , Gentlemen are the opinions upon which

I base my facts!” -Sir Winston Churchill

Editorial by DeAnda- “In the face of conflicting Editorial by DeAnda- “In the face of conflicting “facts” and numerous opinions, it appears that “facts” and numerous opinions, it appears that the best course of action remains to adhere to the best course of action remains to adhere to individual responsibilities.” JCTVS individual responsibilities.” JCTVS 2008;135:492-42008;135:492-4

Pagano et al. Bleeding in cardiac surgery: The Pagano et al. Bleeding in cardiac surgery: The use of aprotinin does not affect survival. JCTVS use of aprotinin does not affect survival. JCTVS 2008;135:495-502 7836 patients over 9 years.2008;135:495-502 7836 patients over 9 years.

JCTVS March 2008JCTVS March 2008 Westaby S. Aprotinin: twenty-five years of claim Westaby S. Aprotinin: twenty-five years of claim

and counterclaim. JCTVS;2008:135:487-91.and counterclaim. JCTVS;2008:135:487-91.

Koster A et al. High dose aprotinin effectively Koster A et al. High dose aprotinin effectively reduces blood loss during on-pump coronary reduces blood loss during on-pump coronary artery bypass grafting with bivalirudin artery bypass grafting with bivalirudin anticoagulation. JCTVS 2008;135:685-7.anticoagulation. JCTVS 2008;135:685-7.

Iwata Y et al. Aprotinin confers neuroprotection Iwata Y et al. Aprotinin confers neuroprotection by reducing excitotoxic cell death. JCTVS by reducing excitotoxic cell death. JCTVS 2008;135:573-8.2008;135:573-8.

Meta-analysis & ObservationalMeta-analysis & Observational

0.1 1 10Odds Ratio

Cerebrovascular

Renal

MI/Cardiovascular

Death

SedrakyanCochrane Mangano

Renal Injury, Hemodilution and Renal Injury, Hemodilution and TransfusionTransfusion

Retrospective 1760 PtsRetrospective 1760 Pts Single centerSingle center 31% female31% female CABG with CPBCABG with CPB Major Outcome: Delta CreatinineMajor Outcome: Delta Creatinine Renal Injury= Delta Creatinine >50%Renal Injury= Delta Creatinine >50% Acute Renal Failure=100% increase in Creatinine and > Acute Renal Failure=100% increase in Creatinine and >

2.1mg/dl.2.1mg/dl. Anemia associated with renal failure

Habib R et al. Role of Hemodilutional Anemia and Transfusion during Cardiopulmonary Bypass in Habib R et al. Role of Hemodilutional Anemia and Transfusion during Cardiopulmonary Bypass in Renal Injury After Coronary Revascularization: Implications on Operative Outcome. Critical Care Renal Injury After Coronary Revascularization: Implications on Operative Outcome. Critical Care Medicine 2005;33:1749-56. Medicine 2005;33:1749-56.

Propensity Analysis: Tx and Cr Propensity Analysis: Tx and Cr ChangeChange

% Change Cr.% Change Cr. 0.0029 0.0029%Cr-Clearance %Cr-Clearance 0.0043 0.0043Renal InjuryRenal Injury 0.0030 0.0030ARF ARF 0.0010 0.0010LOSLOS 0.0027 0.0027

Habib R et al. Role of Hemodilutional Anemia and Transfusion Habib R et al. Role of Hemodilutional Anemia and Transfusion during Cardiopulmonary Bypass in Renal Injury After Coronary during Cardiopulmonary Bypass in Renal Injury After Coronary Revascularization: Implications on Operative Outcome. Critical Care Revascularization: Implications on Operative Outcome. Critical Care Medicine 2005;33:1749-56. Medicine 2005;33:1749-56.

EditorialEditorial

Spiess BD. Choose One: Damned if you Spiess BD. Choose One: Damned if you do/Damned if you don’t. Critical Care Medicine do/Damned if you don’t. Critical Care Medicine 2005 (in press).2005 (in press).

Both Low Hct and Tx are implicated in adverse Both Low Hct and Tx are implicated in adverse events.events.

Tx makes it worse, not better.Tx makes it worse, not better. Blood Conservation is the Answer!Blood Conservation is the Answer!

Habib R et al. Role of Hemodilutional Anemia and Transfusion during Habib R et al. Role of Hemodilutional Anemia and Transfusion during Cardiopulmonary Bypass in Renal Injury After Coronary Revascularization: Cardiopulmonary Bypass in Renal Injury After Coronary Revascularization: Implications on Operative Outcome. Critical Care Medicine 2005;33:1871-4.Implications on Operative Outcome. Critical Care Medicine 2005;33:1871-4.

What About BART?What About BART?

Not published yet!Not published yet!Mortality data is being adjudicated!Mortality data is being adjudicated!

But, don’t judge until it is published!But, don’t judge until it is published!

Evidence BasedEvidence Based

“… “… the science of medicine becomes a the science of medicine becomes a structuredstructured and organized way of using and organized way of using probabilityprobability…to best benefit the …to best benefit the patient patient and the and the communitycommunity.”.”

Jenicek M. Foundations of evidence-based medicine. New York: Parthenon Pub. Jenicek M. Foundations of evidence-based medicine. New York: Parthenon Pub. Group. 2002.Group. 2002.

ConclusionsConclusions

What is the significance of “transient” creatinine changes??

Should we wait for BART?Should we wait for BART? Will Bart answer everything?Will Bart answer everything? What if Bart does not answer anything?What if Bart does not answer anything? How much to blame are we all?How much to blame are we all? How do you assure drug safety?How do you assure drug safety? Do we determine medical care by “60 Minutes”, threat of

medical legal action? What is the sociology of this “research”? Do you feel like betting on this one?

How are you going to bet on this How are you going to bet on this one? What are we teaching our one? What are we teaching our kids (students, public, patients)?kids (students, public, patients)?