MISADVENTURES IN MEDICAL JUDGMENT

ALAN D. FORKER, MD, FACPPROFESSOR OF MEDICINE, UNIV MO-KC

DIRECTOR, OUTPT LIPID DIABETES RESEARCH,

MIDAMERICA HEART INSTITUTE OF SAINT LUKES HOSPITALKANSAS CITY, MO

FINANCIAL DISCLOSUREFINANCIAL DISCLOSURE

• Speakers Bureau:– Merck– Tekada

• Research support:– Merck – Tekada – Novartis – Reliant – Phenomix – ISIS – Sanofi Aventis -Boehringer Ingelheim-InteKrin-Roche

Satchel Paige said:Satchel Paige said:““ItIt’’s not just what you dons not just what you don’’t t

know that hurts you, itknow that hurts you, it’’s what s what you think you know that just you think you know that just

ainain’’t so.t so.””

““DONDON’’T WORRY ABOUT T WORRY ABOUT CALCULATING LV EJECTION CALCULATING LV EJECTION

FRACTION (EF).FRACTION (EF).WEWE’’LL NEVER USE IT IN LL NEVER USE IT IN CLINICAL MEDICINE.CLINICAL MEDICINE.””

Robt. FryeRobt. FryeMayo Clinic, 1969Mayo Clinic, 1969

Relationship of Ejection Fraction to Relationship of Ejection Fraction to Cardiac MortalityCardiac Mortality

MossMoss--Bigger Multicenter Postinfarction Research Grouip. NEJM 1983;309Bigger Multicenter Postinfarction Research Grouip. NEJM 1983;309(6):333(6):333

Standard Textbook Advice re:Standard Textbook Advice re:Rx Systemic HypertensionRx Systemic Hypertension

19401940’’s: Dr. Charles Friedbergs: Dr. Charles Friedberg, D, Diseases of the iseases of the HeartHeart

mild mild benignbenign HTN: <200/100; no Rx neededHTN: <200/100; no Rx needed

1950: Dr. Tinsley Harrison 11950: Dr. Tinsley Harrison 1stst EditionEdition““Rx should be based on Sxs coronary difficultiesRx should be based on Sxs coronary difficulties””

M. Moser Jo Clin HTN Aug 2006

Marvin MoserMarvin MoserHistorical Perspectives Rx HTNHistorical Perspectives Rx HTN

19401940’’ssCourse of unRxCourse of unRx’’d HTN: d HTN: President FDRPresident FDR

Jo Clin HTN Aug 2006

FDR: Development Malignant HTN FDR: Development Malignant HTN 19441944--19451945

O’Rourke, Seward Mayo Clinic Proc 2006; 81: 1057-68

““HUGE ADVANCE RX HTN:HUGE ADVANCE RX HTN:

ALDOMET( FDA approved ALDOMET( FDA approved 1968)1968), A FALSE , A FALSE

TRANSMITTER(TRANSMITTER(WRONGWRONG).).SO FEW SIDE EFFECTS,SO FEW SIDE EFFECTS,

DONDON’’T WORRY ABOUT IT.T WORRY ABOUT IT.””

Alan D. Forker, MDAlan D. Forker, MDLincoln, NE 1971Lincoln, NE 1971

FORKER, YOU FORKER, YOU DING DONG,DING DONG,

II’’M IMPOTENT!M IMPOTENT!

Hypertension Rx Teaching 1963

• Age 60-70 year old patient• BP=180-190/80 mm Hg• “Patient does not need BP

lowering Rx, since the diastolic pressure is normal.”

Slide SourceHypertensionOnline

www.hypertensiononline.org

0255075

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Systolic BP and CV Death in MRFITSystolic BP and CV Death in MRFIT

Nondiabetic (n=342,815)

Diabetic (n=5,163)

<120 120-139

Systolic BP (mmHg)

140-159 160-179 180-199 ≥200

Stamler J, et al Diabetes Care 1993; 16 : 434-444

Will Rogers said:

Good judgment comes from experience,

and a lot of that comes from bad judgment.

“Systolic pressure is all that matters” > 50 yrs

B.Williams, et al (Editorial) Lancet June 28,2008

GET TO GOALGET TO GOAL

Not only BPNot only BPAlso HbA1CAlso HbA1C

LDL, TG, & HDLLDL, TG, & HDLProteinuriaProteinuria

LVHLVH

Combo Rx Taboo

• PharmD’s prior to JNC VI (pre-2003)– Scientific method: use each drug separately

with individual titration of doses• JNC 7

– Too many patients no goal, too slow– If BP > 20/10 mmHg above goal, start with 2

drugs, including combination drug

““EVERY PATIENT POSTEVERY PATIENT POST--MI MI WITH EF < 40% AND WITH EF < 40% AND

FREQUENT PVCFREQUENT PVC’’S NEEDS S NEEDS ANTIANTI--ARRHYTMIC Rx to ARRHYTMIC Rx to

PREVENT SUDDEN CARDIAC PREVENT SUDDEN CARDIAC DEATHDEATH””

Epidemiologic Data 1960’s→ 1980’s

Cardiac Arrhythmia Suppression Trial (CAST)

GROWING APPRECIATION SIGNIFICANCE GROWING APPRECIATION SIGNIFICANCE LONG QT & TORSADES DES POINTESLONG QT & TORSADES DES POINTES

•• 28 yo F with pure Mitral stenosis with 28 yo F with pure Mitral stenosis with thin pliable leafletsthin pliable leaflets

•• Mitral commissurotomyMitral commissurotomy→→good resultgood result•• Except: postop Atrial fibExcept: postop Atrial fib

–– Rx: Rx: QuinidineQuinidine→→not convertnot convert–– Plan: return in 3 weeks, not NSRPlan: return in 3 weeks, not NSR→→

elecrical cardioversionelecrical cardioversion•• 2 weeks postop: found dead in bed2 weeks postop: found dead in bed

Case from AForker files, 1987

Influence of CASTInfluence of CAST(Announce 1989, Publish 1991)(Announce 1989, Publish 1991)

1)1) Limited role Class I drugsLimited role Class I drugsa)a) Significant HD = Significant HD = ↑↑ mortalitymortality

2)2) Look for drugs with alternative Look for drugs with alternative mechanism action:mechanism action:

a)a) ↑↑ AP duration/ERPAP duration/ERP——AmiodaroneAmiodarone--GESICA in South America: worked GESICA in South America: worked ↓↓ mortalitymortality

b)b) Block sympathetic stimulationBlock sympathetic stimulation----BBlBBl3)3) Trend to Trend to earlier, greater use ICDearlier, greater use ICD

-1994: 4S Trial-- start of the STATIN ERA : lower the LDL, decrease total mortality.

-OOPS! Cerivastatin→32deaths rhabdo→ARF, espec combo with Gemfibrozil

Good news: rare with Fenofibrate

LIPID TRIALS:LIPID TRIALS:GOOD & BAD NEWSGOOD & BAD NEWS

www. Clinical trial results.org

How about the other How about the other ““good Chol or good Chol or HDL?HDL?””–– IsnIsn’’t it obvious from Framingham data t it obvious from Framingham data

that that ↑↑ HDL=HDL=↓↓ morbidity/mortality CADmorbidity/mortality CADOOPSOOPS: Chol Ester Transfer : Chol Ester Transfer ProteinProtein(CETP(CETP) inhibition ) inhibition (Torcetrapib(Torcetrapib))——dramatic dramatic ↑↑ HDL HDL but worse CV outcomesbut worse CV outcomes

LIPID TRIALS:LIPID TRIALS:GOOD & BAD NEWSGOOD & BAD NEWS

Variable and study phase

Atorvastatin plus

Torcetrapib (120 mg/day)

(N=9)

Torcetrapib Alone

(120 mg/day) (N=10)

Torcetrapib Alone

(120 mg twice/day)

(N=6)HDL cholesterol

Study phase (mg/dl)Placebo 29 ± 4 32 ± 7 34 ± 5Torcetrapib 47 ± 10 † 46 ± 14 ‡ 70 ± 15 †

Percentage change 61 46 106HDL2 cholesterol

Study phase (mg/dl)Placebo 2.9 ± 2.6 6.4 ± 3.8 7.6 ± 3.2Torcetrapib 11.0 ± 4.3 † 11.1 ± 7.8 § 29.3 ± 13.6 ¶

Percentage change 323 87 283

Plasma HDL Cholesterol Levels at the End of the Placebo and Drug Phases

For comparison with placebo: † P<0.001, ‡ P=0.001, ¶ P=0.004, § P=0.02 Brousseau, M. et al., N Engl J Med 2004;350:1505-15.

ILLUMINATE Trial15,067 pts with CV Dis and/or Diab

Barter, et al NEJM Nov 22, 2007

Barter P et al. N Engl J Med 2007;10.1056/NEJMoa0706628

Causes of DeathILLUMINATE Trial

LIPID TRIALS: GOOD & BAD NEWS

• How about the other “good Chol or HDL?”

• OOPS: Chol Ester Transfer Protein(CETP) inhibition (Torcetrapib)—dramatic ↑ HDL but worse CV outcomes

–↑ Syst BP mean 5.4 mmHg–2 other companies (Merck, Roche)

working on CETP inhibitor: no ↑ BP effect

• Is it Quantity or Quality of HDL particle??

• ADMIT(2000), HATS(2001), ADVENT(2002)• Niacin flushing receptor inhibitor• ↑ Glucose 10-20 mg/dl first 4 weeks in Diab 2

– BUT only 4 mg/dl ↑ at 24 weeks, and HbA1c only ↑ 0.2%

• Combo with Statin: HPS2-THRIVE– CV outcomes in 20,000 pts

LEADING TO RESURGENCE INTEREST NIACIN

JUST GIVE ME THE NUMBERS

– I tell Dr. John Bengston(1971): “Can’t have acute pulmonary edema. She has a normal heart size on chest Xray, and her echo( M mode) shows a EF=55%.”• 58 F Diabetic type 1. No Hx chest

pain.• I observe her going into a 2nd

episode!!• Cath: 3 vessel CAD→successful

CABG

M.Konstam Jo Card Failure 2003; 9: 1-3

Pathophysiology Diastolic CHFPathophysiology Diastolic CHF

Choudhury, Gheorghiade, Bonow AJC 2002; 89: 719-22

espec LVH

PREOP EVAL:PREOP EVAL:““DOES THE PATIENT HAVE DOES THE PATIENT HAVE

ANY SIGNS OF CHF?ANY SIGNS OF CHF?””

““I DONI DON’’T KNOW. I CANT KNOW. I CAN’’T FIND T FIND ANY RESULTS OF A BNP!ANY RESULTS OF A BNP!””

3RD Year Internal Medicine Resident, 2005

What has happened to What has happened to Bedside Exam Skills? Bedside Exam Skills?

Elevated JVPElevated JVPPalpable overactive and/or enlarged heartPalpable overactive and/or enlarged heartS3 gallopS3 gallop““Oh, itOh, it’’s just a Grade 2/6 systolic murmur. s just a Grade 2/6 systolic murmur. Let me check the echo report.Let me check the echo report.””HepatomegalyHepatomegaly

• 70 F 3 weeks post-CABG with marked fluid retention, 25# Wt gain. – preop EF=normal

• ↑↑ JVP; RV lift without palpable LV; ↑ S2P; no S3; EF=52%. ECG: nonspecific, but rightward axis; no new or old infarct

• Finally put in S-Ganz cath: PA wedge=3 mm Hg!PA=75 mm Hg

• CT chest: severe, diffuse pulmonary diseasewith multiple bullae, ie has Cor Pulmonale

“GOT TO BE LV FAILURE; THE BNP=1,300”

WHAT DOES THE FUTURE OF WHAT DOES THE FUTURE OF MEDICINE LOOK LIKE?MEDICINE LOOK LIKE?

BEWARE OF HIGH TECH FADSBEWARE OF HIGH TECH FADS

Got a PFO: put in an atrial Got a PFO: put in an atrial septal occlusion deviceseptal occlusion deviceGot AFib: ablate it.Got AFib: ablate it.Got a Plaque: stent it. Got a Plaque: stent it.

BEWARE OF FADS IN BEWARE OF FADS IN MEDICINE #1MEDICINE #1

Should PFO with TIA/Stroke have clam Should PFO with TIA/Stroke have clam shell device?shell device?

Investigator banned after Investigator banned after >100 cases; highest in rest of >100 cases; highest in rest of US was 15!US was 15!?? Migraine headaches?? Migraine headaches

? ? ↓↓ number and severity of HAnumber and severity of HA’’ss

Hijazi ACC Cardiosource Jan 2006

Randomized Controlled Trials Comparing PFO Device Closure vs A/C in Cryptogenic Stroke/TIA, or Migraine HA’s

Migraine Intervention with Migraine Intervention with STARFlex Technology (MIST)STARFlex Technology (MIST)

• Must have Migraine with aura, start < age 50– >5 HA days/month– failed 2 classes drugs

• Echo eval Right→Left shunt at PFO: # bubbles– neg=0; small < 10; mod=10-20; large >

20– excluded if neg or small

• Sham procedure: skin incision in the groin Dowson, et al Circulation March 18, 2008

• 163/432 (38%) had mod-large R→L shunt

–147 randomized• Primary endpt: HA cessation

–no difference ( 3/74 vs 3/73)• Secondary endpts: change in severity,

frequency, characterics, & quality of life

–no significant difference

Migraine Intervention with Migraine Intervention with STARFlex Technology (MIST)STARFlex Technology (MIST)

Dowson, et al Circulation March 18, 2008

Overview of 2007 FDAOverview of 2007 FDACirculatory Devices Panel MeetingCirculatory Devices Panel Meeting

• “Off label” closure should be discouraged• “Despite the fact that PFO closure is clearly

not the standard of care after a first cryptogenic stroke, it is believed to be commonly done.”

• Patients and Physicians should be educated about the lack of evidence

Slottow, Steinberg, Waksman Circ 2007; 116: 677-82

BEWARE OF FADS IN BEWARE OF FADS IN MEDICINE #2MEDICINE #2

•Ablate LA/PV to “cure” AFib?

–Remember: AFFIRM trial•no difference mortality NSR vs Rate control

AFFIRM: RATE CONTROL vsAFFIRM: RATE CONTROL vsRHYTHM CONTROL/CARDIOVERSIONRHYTHM CONTROL/CARDIOVERSION

New Engl Jo Med 2002; 347: 1825-33

75 F Convinced She needs 75 F Convinced She needs AFib AblationAFib Ablation

• Totally asymptomatic after first episode AFib, now NSR; on Warfarin

• No serious structural heart disease, but very concerned re: “MVP”– several ER visits for atyp chest pain– Cor angios: normal

• Adamant “I can’t stay on Warfarin, that rat poison”

Indication for AFib AblationIndication for AFib Ablation

• Paroxysmal or Persistent AFib• Significant symptoms• Recurrent Afib despite Rx trial with at

least 1 Class Ic or Class III antiarrhythmic• “Refusal to take Warfarin is not an

acceptable rationale”

Calkins, Brugada, Packer, et al

HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fib.

Heart Rhythm 2007; 4(6): 816-861

Key Finding: Myocardial sleeves Key Finding: Myocardial sleeves extend 6extend 6--14 mm into PV14 mm into PV’’ss

J. Marine JAMA 2007; 298: 2768-78

Ablation Sites around PVAblation Sites around PV’’ss

J. Marine JAMA 2007; 298: 2768-78

PROBLEM:PROBLEM:MANY PATIENTS HAVE MANY PATIENTS HAVE

ARRHYTHMOGENIC FOCI ARRHYTHMOGENIC FOCI ELSEWHERE, NOT JUST IN THE PVELSEWHERE, NOT JUST IN THE PV’’SS

LEARNING CURVE:LEARNING CURVE:HIGH % DEVELOP RECURRENCE;HIGH % DEVELOP RECURRENCE;

FREQUENT NEED REPEAT FREQUENT NEED REPEAT PROCEDURESPROCEDURES

75 F Convinced She needs 75 F Convinced She needs AFib AblationAFib Ablation

• Totally asymptomatic after first episode AFib, on Warfarin; now NSR

• No serious structural heart disease, but very concerned re: “MVP”– several ER visits for atyp chest pain– Cor angios: normal

• Adamant “I can’t stay on Warfarin, that rat poison”

• 6 months post-ablation: embolic stroke with recurrent AFib, off A/C

Worldwide AFib Ablation SurveyWorldwide AFib Ablation Survey

• Success rates 37-95%– mean ~ 70%

• Freedom from AFib without antiarrhythmic drugs: 4550 of 8745 pts or 52%

• Freedom from AFib with antiarrhythmics and repeat procedures included: 76%

• vs F.Morady, Univ Michigan– 147 pts, 70% NSR, very few complications,

including no strokes or deaths.

Cappato, Calkins, Chen,et al Circ 2005; 111: 1100-05

AFIB ABLATIONAFIB ABLATIONIDEAL CANDIDATEIDEAL CANDIDATE

• YOUNG• PAROXYSMAL AFib• ABSENCE SIGNIFICANT UNDERLYING HEART

DISEASE– NORMAL OR ONLY MILD LAE

• Shorter duration if persistent AFib

•Performed at experienced, high volume center

You must discuss You must discuss COMPLICATIONSCOMPLICATIONS thoroughlythoroughly

• 6% rate of major complications– thromboembolism 7%– PV stenosis 1.3%– pericardial tamponade 1.2%– stroke 1.0%– phrenic nerve injury 0.2%– atrial-esophageal fistula 0.1-0.2%

• usually fatal• Vascular access complications most frequent

– up to 3 catheters inserted thru femoral vein– need 2 transseptal punctures

J. Marine JAMA 2007; 298: 2768-78

Complications of AFib AblationComplications of AFib Ablation

• Local hospital Kansas City

–major incidence of pericardial tamponade

• that Electrophysiologist no longer working in that practice/hospital.

•Plaque is a Plaque—they all need PCI, don’t they? Just a matter of plumbing and clogged pipes?–Have you heard about the COURAGE trial?•chronic stable angina

BEWARE OF FADS IN BEWARE OF FADS IN MEDICINE #3MEDICINE #3

Top 10 AHA Advances for 2007Top 10 AHA Advances for 2007

•COURAGE study #2

•Note: not include pts with Acute Coronary Syndrome

Boden, O’Rourke, Teo, et alOptimal medical therapy with or without PCI

for stable coronary disease.NEJM 2007; 356: 1503-16

COURAGE: Treatment effect on COURAGE: Treatment effect on primary outcomeprimary outcome

HR 1.05*(0.87-1.27)P = 0.62

Boden WE et al. N Engl J Med. 2007;356.

All-cause death, MI

*Unadjusted

Medical therapy PCI + medical therapy

No. at riskMedical therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35

Survival free of primaryoutcome

0 2 4 70

0.5

0.6

0.7

0.8

1.0

0.9

Years6531

STABLE SURVIVORS ACUTE MISTABLE SURVIVORS ACUTE MIMEDICAL vs REVASCULARIZEMEDICAL vs REVASCULARIZE

Mahmarian, et al JACC 2006; 48: 2458-67

Medical or PCI ?

STABLE SURVIVORS ACUTE MISTABLE SURVIVORS ACUTE MIMEDICAL vs REVASCULARIZEMEDICAL vs REVASCULARIZE

Mahmarian, et al JACC 2006; 48: 2458-67

n=101

n=104n=104

WE ARE NOT JUST PLUMBERS!WE ARE NOT JUST PLUMBERS!

• Atherosclerosis is not just a >50% plaque, with a large lipid core

• Genetic factors/Famliy History• Endothelial dysfuntion/Nitric Oxide

– Global or all CV risk factors• Inflammatory process

– Vulnerable vs Stable plaque• Blood: thrombotic vs lytic• Vasomotion

• Talk about a Fad: when short acting Nifedipine first came on the market: “All heart attacks have an element of spasm”

• 3 trials acute MI: all ↑ mortality!

Somedays it would be comforting to feel this Somedays it would be comforting to feel this powerful, especially with life or death powerful, especially with life or death

decisions pendingdecisions pending

Satchel Paige said:Satchel Paige said:““ItIt’’s not just what you dons not just what you don’’t t

know that hurts you, itknow that hurts you, it’’s what s what you think you know that just you think you know that just

ainain’’t so.t so.””

ADFADF’’s Advice after 43 yrs Experiences Advice after 43 yrs Experience

Daily dose of humble pie is mandatoryDaily dose of humble pie is mandatoryWe make mistakesWe make mistakes

wewe’’re only humanre only humandondon’’t beat yourself t beat yourself upup→→forgive yourself NOWforgive yourself NOW

Be open to discussion with peers, family, Be open to discussion with peers, family, friendsfriends→→you are you are not alone.not alone.Spiritual Life keySpiritual Life key→→whetherwhether church, prayer, meditation, walk church, prayer, meditation, walk the labyrinth, Tai Chi, Yoga, music, art, petsthe labyrinth, Tai Chi, Yoga, music, art, petsKeep a Keep a Learning PortfolioLearning Portfolio→→introspectiveintrospective analysis of your analysis of your strengths/weaknessesstrengths/weaknesses

Keep LearningKeep LearningAnd move on, hopefully without Addiction to Perfection, EtoH, And move on, hopefully without Addiction to Perfection, EtoH, and/or Drugsand/or Drugs