heartbeat – apr 2002 triumph of the trials triumph of the trials: acc 2002 valentin fuster md...

Heartbeat – Apr 2002

Triumph of the trials

Triumph of the trials: ACC 2002

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York

Christopher Cannon MDCardiologistBrigham and Women's HospitalBoston, Massachusetts

James Ferguson MDAssociate Director, CardiologySt Luke's Episcopal Hospital and Texas Heart InstituteHouston, Texas

Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, New York



MADIT IIICDs for post-MI patients

with low EF

Atrial fibrillationRate vs rhythm

Coated stentsThe end of restenosis?

Subjects



MADIT II

Multicenter Automatic Defibrillator Implantation Trial II

1232 post-MI patients with moderate LV dysfunction (EF 30%) randomized to ICD or conventional medical therapy

Arrhythmia was not an inclusion criteria, did not require previous EP testing



Moss et al. N Engl J Med 2002;346(12):877-83.

MADIT II: All-cause mortality

0%

5%

10%

15%

20%

25%

ICD Medical therapy

14.2%

19.8%P=0.016



HospitalizationsICD group had more

hospitalizations

Drug treatmentThe patients received the

proper drug regimen

CostDo we put ICDs in everyone?

MADIT II: Additional discussion



MADIT II: Diverging curves

5-46283 years

Time

4-46282 years

-47-20121 year

Nominal 95% CI

Percent reduction in rate of death on

ICD therapy




MADIT II: Increased hospitalizations

Patient group

11.3148 (19.9%)Defibrillator group

9.473 (14.9%)Conventional therapy group

# patients hospitalized/1000

hours follow-up# patients

hospitalized


Nominal p=0.09

"If you save lives in sick people, they are going to require more hospital resources."

Ferguson



MADIT II: Medications

64%67%Statins

Medication at last contact

70%70%Beta-blockers

72%68%ACE-inhibitors

Medical therapy (n=490)

ICD (n=742)

81%72%Diuretics




MADIT II: Performance

We don't yet have details on how often the ICDs actually fired in the patients.

VENTAK PRIZM 2 ICDSource: Guidant



MADIT II: Mortality by event

46 (9.4%)27 (3.6%)Arrhythmic

Cause of death

6774Cardiac

2026Noncardiac

Medical therapy (n=490)

ICD (n=742)

1841Nonarrhythmic




MADIT II: Fuster's hypothesis

"I bet that what is happening is the group that otherwise might have been induced into ventricular tachycardia is the group that has benefit."

Fuster




• EF < 40% • CAD • spontaneous nonsustained ventricular tachycardia (VT-NS)

MADIT-II: MUSTT

Mortality at 5 years

ICDs (n=161)

Drug therapy (n=153)

P value

Total mortality 24% 55% <0.001

Buxton et al. N Engl J Med 1999;341(25):1882-90.

Entry Criteria



MADIT II: The patient

Patient with low EF, previous MI, and the patient asked for a defibrillator ICDs cost $25-35,000

Found a normal result on signal-averaging, so I sent him home

FusterVENTAK PRIZM 2 ICDSource: Guidant



"The idea of risk stratification to try and identify those who benefit most has become absolute dogma in clinical practice in acute coronary syndromes."

Cannon

MADIT II: Risk stratification

•Inducibility makes sense as a good marker of the risk of arrhythmic death

•How recent is the MI?

•Arrhythmic burden might be useful



MADIT II: True costs

• We will eventually have to have risk stratification

• What is cost/quality of year of life saved?

• We need data extending out for 2-3 years

Weber



MADIT II: Science takes its course

Weber

"The truth is that whenever we do anything that prolongs life we are going to be rewarded by horrifying increases in cost. And if we save them completely from heart disease they are going to get cancer."

"In a way it's a futile and frustrating discussion."



MADIT II: Extending the boundaries

What we're doing is defining the boundaries of where ICDs work and don't work

"What MADIT II has done is take the stake and move it a little farther out in terms of post-MI patients with low ejection fraction."

Ferguson



MADIT II: Drilling into the data

We will find a population that benefits and a population that does not

Inducible VT is a completely reasonable hypothesis for defining the benefit population

Putting ICDs in everyone who qualifies for MADIT is "potentially backbreaking"

Ferguson



MADIT II: Signal-averaging

Used signal-averaging because it was a strong predictor of high-risk in MUSTT

At this point in time, don't put an ICD in patients who qualify for MADIT II who have normal signal-averaging

"We have to face these patients today."

Fuster



MADIT II: QRS interval

QRS interval Hazard ratio


0.2 0.4 0.6 0.8 1.0 1.2

< 0.12 sec

0.12-0.15 sec

>0.15 sec

Defibrillator better

Conventional therapy better



MADIT II: Assessing patients

Weber

We don't have enough information to predict who will benefit most

"Seat of the pants indicators" such as QRS intervals or the number of extra systoles should be helpful for now




MADIT II: Fundamental approach

"The fundamental approach that one takes with these patients is 'are they guilty until proven innocent' or are they 'innocent until proven guilty'?"

"Am I going to put a defibrillator in this guy unless there is a reason not to or do I require a reason to put a defibrillator in this individual?"

Ferguson



MADIT II: Reasons to put an ICD in

"I still need a reason to put a defibrillator in an individual."

• Signal-averaged ECG

• Frequency of VPDs

• Heart-rate variability is a possibility

• Probably would not take someone to provocative EP testing

Ferguson



MADIT II: Cost

MADIT II entry criteria would lead to an additional 300,000 patients for ICDs, a $9 billion market

ICDs cost $25-35,000

"When you have something good, industry competes and costs go down."

Fuster




As demand grows, costs should drop

These ICDs are the "BMW 7-series" versions, with all the hi-tech bells and whistles

Cheaper, simpler ICDs could be used in patients with uncomplicated arrhythmic history

Cannon

MADIT II: Cheaper ICDs



MADIT II: Lay press concerns

Extending Life, Defibrillators Can Prolong Death

Could we unintentionally torture patients with ICDs?

Rare, but not impossible



Atrial fibrillation : Quality of Life

While making guidelines, everyone said that AFFIRM and RACE would give all the answers

"I was disappointed"

The issue is quality of life, not mortality, but that wasn't studied



Atrial fibrillation : AFFIRM design

Atrial Fibrillation Follow-up Investigation of Rhythm Management

Conducted at 213 centers in the US and Canada

Randomized 4060 patients to rate control therapy or to rhythm control therapy

All patients enrolled in the trial were able to tolerate either rate or rhythm control therapy at baseline



Atrial Fibrillation: AFFIRM results

P value Endpoint

8479Stroke

356306Mortality

Rhythm Control

Rate control

0.058

NS

Wyse DG, ACC 2002



Atrial Fibrillation: RACE design

RAte Control vs Electrical cardioversion for persistent atrial fibrillation (RACE)

522 patients randomized to medical rate control (n=256) or electrical cardioversion rhythm control (n=266)

3 years follow-up

Primary endpoints: morbidity and mortality

Secondary endpoints: quality of life and cost of therapy



Atrial Fibrillation: RACE results

Endpoint

6.7%7.0%

22.6%17.2%Combined mortality and morbidity*

Rhythm Control (n=266)

Rate control (n=256)

*cardiovascular death, hospitalization for heart failure, thromboembolic complications, severe bleeding, pacemaker implantation, or severe drug side effects

Cardiovascular mortality



Atrial fibrillation : No answers

My original question wasn't answered

Patients with systolic or diastolic dysfunction who don't have atrial kick weren't included in the study

Fuster



Atrial fibrillation : Disappointing

"I'm not an electrophysiologist, so I've been waiting for guidelines to tell me what to do for some time."

"It's a little disappointing that […] those people who might have benefited probably didn't even get into the study."

Weber



Atrial fibrillation : AFFIRM drugs

Rhythm control

• amiodarone (39%)

• sotalol (33%)

• propafenone (10%)

Ablation and pacemakers were given in the rhythm arm, if necessary



Atrial fibrillation : AFFIRM drugs

Rate control

• digoxin (51%)

• beta-blockers (49%)

• calcium-channel blockers (41%)

There was no specific drug regimen



Atrial fibrillation : Drug safety

"At least the drugs that maintained normal sinus rhythm didn't kill the patients."

Maybe amiodarone is protective

Fuster

It could be that the fact these were patients with atrial fibrillation played a role

Ferguson



Atrial Fibrillation: Low mortality

Patients who need atrial kick are the toughest atrial fibrillation patients to work with

The good news is mortality favored rate control slightly – this looks pretty safe

Cannon



"I came away with the notion that A-Fib and coumadin are very good partners."

Most strokes in AFFIRM occurred in patients who either stopped warfarin or had an INR below 2.0

The idea you should convert A-Fib patients so they can get off anti-coagulation doesn't hold up

Atrial Fibrillation: Warfarin

Cannon



"The concept that you convert to normal sinus rhythm and therefore off of anticoagulants is really a dream."

I do Holter monitoring 3 months later because most patients you can see there are still a few beats of atrial fibrillation

Atrial fibrillation : Anticoagulation

Fuster



Atrial fibrillation developing after cardiac surgery often reverses itself

You should still follow up patients with a Holter to document that the patient has stable sinus rhythm

Atrial Fibrillation: Anticoagulation

Cannon



The guidelines urge great caution about discontinuing anticoagulants

You should continue anticoagulation unless something convinces you otherwiseACC/AHA/ESC GUIDELINES FOR THE MANAGEMENT OF

PATIENTS WITH ATRIAL FIBRILLATIONJ Am Coll Cardiol 2001;38:1266i-1xx

Atrial Fibrillation: Guidelines

Fuster



"The big winner in this seemed to be coumadin. Because if you want to use rhythm control because you think you are reducing the need for anticoagulation you're probably making a mistake."

Atrial fibrillation: Anticoagulation

Ferguson



Coated stents: FIM

Measurement at 24 months

Fast release formula

Slow release formula

Late loss 0.32 mm -0.09 mm

Restenosis rate 0% 0%



Coated stents: RAVEL

Measurement at 12 months

Sirolimus (n=??)

Control (n=??)

Event-free survival

94.2% 71.2%

Late loss -0.01 + 0.33 0.80 + 0.53

Restenosis rate 0% 26%



"[Ending restenosis] is an idea people have been looking for, and stopping cell growth locally looks like a real winner."

Coated stents: Stopping cell growth

Cannon



"It's probably a victory for vascular biologists everywhere to say the shotgun approach or crude approaches we've used in the past have not worked."

Not all coated stents will work, we need to look long at hard at the data

We need to look at the SIRIUS trial

Coated stents: Stopping cell growth

Ferguson



Brazil data makes you believe the subsequent pathology is determined at the time of procedure

"I assume most of the value of the coated stent is a local effect that takes place soon after the stent is put in."

Coated stents: Early pathology

Weber



Coated stents: New study

>2000 pts

Diabetics with multi-vessel disease lesions (15-30 mm long, 2.5-3.5 mm diameter)

Randomized to sirolimus stent or CABG

This study has been submitted to NIH and is under consideration



Finding clinical effect on high-risk patients is the most important study to do

• BARI used balloon angioplasty without antiplatelet therapy

• Can diabetics with multi-vessel disease be stented or must they use surgery?

• It even raises questions about stenting patients with stable angina

Coated stents: End of CABG?

Cannon



Coated stents: 6-month QCA in diabetics

Measurement Sirolimus (n=19)

Control (n=25) P value

Mean luminal diameter

2.31 mm 1.56 mm <0.0001

Late loss 0.08 0.82 <0.0001

Diameter stenosis

16% 38% <0.0001

Restenosis rate 0% 42% <0.0001



Coated stents: Patient

What do you do with this patient?

• Had 3 previous PCIs in the circumflex artery

• Currently has a 1.5-cm lesion in the circumflex artery

Do you send him to Europe to get the sirolimus-coated stent or do you use radiation?



I would go with beta-radiation therapy

• Reduces in-stent restenosis by about 50%

• Coated stents have not shown favorable results for in-stent restenosis

Coated stents: Radiation advantage

Cannon



Some issues still need to be answered with radiation therapy

"What are you doing to the biology of the vessels and do you change how they are going to respond in the future if in fact you don't prevent restenosis?"

Coated stents: Radiation questions

Ferguson



MADIT IIICDs for post-MI patients

with low EF

Atrial fibrillationQuantity and quality of life

Coated stentsThe end of restenosis?

Conclusions: Subjects



Coated stentsMarrying mechanical approachand an understanding biology

Atrial fibrillationRhythm control doesn't mean you stop anticoagulation

ICDsPoint out our need to apply techniques of risk stratification

Conclusions: Ferguson

Ferguson



Conclusions: Weber

Weber

Coated stentsIt won't be long before thecoated stent is the only way to go

Atrial fibrillationOne word: coumadin

ICDsWe still need to learn moreabout which patients are the best subjects



Conclusions: Cannon

Cannon

A triumph for trials guiding appropriate therapy

Ventricular tachycardia: Devices

Coronary stenosis: Devices and medicine married together

Atrial fibrillation: Medicine is the right answer



It's an exciting time, but how much could we accomplish if we could move forward even more in primary prevention?

Conclusions: Fuster

Fuster

heartbeat – apr 2002 triumph of the trials triumph of the trials: acc 2002 valentin fuster md...

Documents

trials triumph

trials madit

trials moss

trials ef

guidant slide

ferguson slide

drug therapy n

n engl j med